Christine K. O’Neil
LEARNING OBJECTIVES
Upon completion of the chapter, the reader will be able to:
1. Identify characteristics of the types of pain—nociceptive, inflammatory, neuropathic, and functional.
2. Explain the mechanisms involved in pain transmission.
3. Select an appropriate method of pain assessment.
4. Recommend an appropriate choice of analgesic, dose, and monitoring plan for a patient based on type and severity of pain and other patient-specific parameters.
5. Perform calculations involving equianalgesic doses, conversion of one opioid to another, rescue doses, and conversion to a continuous infusion.
6. Educate patients and caregivers about effective pain management, dealing with chronic pain, and the use of nonpharmacologic measures.
KEY CONCEPTS
Pain is an unpleasant, subjective experience that is the net effect of a complex interaction of the ascending and descending neurons involving biochemical, physiologic, psychological, and neocortical processes.
Following initial assessment of pain, reassessment should be done as needed based on medication choice and the clinical situation.
Effective treatment involves an evaluation of the cause, duration, and intensity of the pain and selection of an appropriate treatment modality for the pain situation.
Whenever possible, the least potent oral analgesic should be selected.
Equianalgesic doses should be used when converting from one opioid to another.
INTRODUCTION
Pain is defined by the International Association for the Study of Pain (IASP) as “an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage.”1 Pain is an unpleasant subjective experience that is the net effect of a complex interaction of the ascending and descending neurons involving biochemical, physiologic, psychological, and neocortical processes. Pain can affect all areas of a person’s life including sleep, thought, emotion, and activities of daily living. Because there are no reliable objective markers for pain, the patient is the only person who can describe the intensity and quality of their pain.
Pain is the most common symptom prompting patients to seek medical attention and is reported by more than 80% of individuals who visit their primary care provider.1 Despite the frequency of pain symptoms, individuals often do not obtain satisfactory relief of pain. This has led to recent initiatives in health care to make pain the fifth vital sign, thus making pain assessment equal in importance to obtaining a patient’s temperature, pulse, blood pressure, and respiratory rate.
EPIDEMIOLOGY AND ETIOLOGY
Prevalence of Pain
Most people experience pain at some time in their lives, and pain is a symptom of a variety of diseases. For some, pain might be mild to moderate, intermittent, easily managed, and have minimal effect on daily activities. For others, pain might be chronic, severe or disabling, all consuming, and treatment resistant. Thus, identifying the exact prevalence of pain is a difficult task. According to the American Pain Foundation, more than 76 million people in the United States suffer from chronic pain, and an additional 25 million experience acute pain from injury or surgery.2 About 26% of the adults, mostly women and the elderly, experience chronic pain such as back pain, headache, and joint pain.
Prevalence rates for a variety of different types of pain have been described. Approximately one quarter of U.S. adults reported having low back pain lasting at least 1 day in the past 3 months.3 Migraine affects more than 28 million Americans, and 78% of Americans experience a tension headache during their lifetime.4 Pain resulting from fibromyalgia affects 10 million Americans.5 Pain ranges in prevalence from 14% to 100% among cancer patients. Cancer is commonly associated with both acute and chronic pain and about 50% to 70% of those in active treatment will experience significant pain.6
The prevalence of neuropathic pain is unknown because of the lack of epidemiologic studies. Current estimates suggest that approximately 1.5% of the population in the United States might be affected by neuropathic pain.7However, this figure is probably an underestimate and will likely increase due to the increase in disorders associated with neuropathic pain in the ever-growing older population. Approximately 25% to 50% of all pain clinic visits are related to neuropathic pain.8 Central neuropathic pain is estimated to occur in 2% to 8% of all stroke patients.9
The elderly, defined as people 65 years of age and over, bear a significant burden of pain, and pain continues to be under-recognized and undertreated in this population. The prevalence of pain in people older than 60 years is twice that in those younger than 60 years.10 Studies suggest that 25% to 50% of community-dwelling elderly suffer pain. Pain is quite common among nursing home residents. It is estimated that pain in 45% to 80% of nursing home patients contributes to functional impairment and a decreased quality of life.11
The financial impact of pain is considered to be significant. Low back pain alone is responsible for direct medical costs of more than $26 billion annually in 1998 and as much as $50 billion per year in indirect costs.12 The American Productivity Audit of the U.S. workforce, conducted from 2001 to 2002, revealed that the cost of lost productivity due to arthritis, back pain, headache, and other musculoskeletal pain was approximately $80 billion per year.13
Undertreatment of Pain
Despite the growing emphasis on pain management, pain often remains undertreated and continues to be a problem in hospitals, long-term care facilities, and the community. In one series of reports, 50% of seriously ill hospitalized patients reported pain; however, 15% were dissatisfied with pain control, and some remained in pain after hospitalization.14,15
Misconceptions about pain management, both from patients and health care providers, are among the most common causes of analgesic failure. Some clinicians might be hesitant to treat pain because either they do not believe the patient’s reports of pain or feel the patient is exaggerating symptoms in order to obtain medications. Inadequate clinical knowledge of available pain management strategies, including pharmacologic, nonpharmacologic, and alternative therapy options, also often leads to suboptimal pain management. In one survey, approximately three-fourths of physicians cited low competence in pain assessment as the major barrier to effective pain management.16Concerns about opiate misuse, abuse, and diversion also contribute to less than optimal pain management and cause providers to exercise caution when prescribing opiates for pain. Misunderstandings about the terms addiction, physical dependence, tolerance, and pseudoaddiction are additional obstacles to optimal pain management.
Patients might present barriers to pain management by not reporting pain symptoms because of fear of becoming addicted or because of cultural beliefs. Elderly patients might not report pain for a variety of reasons including belief that pain is something they must live with, fear of consequences (e.g., hospitalization, loss of independence), or fear that the pain might be forecasting impending illness, inability to understand terminology used by health care providers, or a belief that showing pain is unacceptable behavior.
PATHOPHYSIOLOGY
Types of Pain
Several distinct types of pain have been described, for example, nociceptive, inflammatory, neuropathic, and functional.17 Nociceptive pain is a transient pain in response to a noxious stimulus at nociceptors that are located in cutaneous tissue, bone, muscle, connective tissue, vessels, and viscera. Nociceptors are classified as thermal, chemical, or mechanical. The nociceptive system extends from the receptors in the periphery to the spinal cord, brain stem, to the cerebral cortex where pain sensation is perceived. This system is a key physiologic function that prevents further tissue damage due to the body’s autonomic withdrawal reflex. When tissue damage occurs despite the nociceptive defense system, inflammatory pain ensues. The body now changes focus from protecting against painful stimuli to protecting the injured tissue. The inflammatory response contributes to pain hypersensitivity that serves to prevent contact or movement of the injured part until healing is complete, thus reducing further damage.
Neuropathic pain is defined as spontaneous pain and hypersensitivity to pain associated with damage to or pathologic changes in the peripheral nervous system as in painful diabetic peripheral neuropathy (DPN), AIDS, polyneuropathy, postherpetic neuralgia (PHN), or in the CNS, that which occurs with spinal cord injury, multiple sclerosis, and stroke. Functional pain, a relatively newer concept, is pain sensitivity due to an abnormal processing or functioning of the CNS in response to normal stimuli. Several conditions considered to have this abnormal sensitivity or hyper-responsiveness include fibromyalgia and irritable bowel syndrome.
Mechanisms of Pain
Pain Transmission
The mechanisms of nociceptive pain are well-defined and provide a foundation for the understanding of other types of pain.18 Following nociceptor stimulation, tissue injury causes the release of substances (bradykinin, serotonin, potassium, histamine, prostaglandins, and substance P) that might further sensitize and/or activate nociceptors. Nociceptor activation produces action potentials (transduction) that are transmitted along myelinated Aδ-fibers and unmyelinated C-fibers to the spinal cord. The Aδ-fibers are responsible for first, fast, sharp pain and release excitatory amino acids that activate α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors in the dorsal horn. The C-fibers produce second pain, which is described as dull, aching, burning, and diffuse. These nerve fibers synapse in the dorsal horn of the spinal cord, where several neurotransmitters are released including glutamate, substance P, and calcitonin gene-related peptide. Transmission of pain signals continues along the spinal cord to the thalamus, which serves as the pain relay center, and eventually to the cortical regions of the brain where pain is perceived.
Pain Modulation
Modulation of pain (inhibition of nociceptive impulses) can occur by a number of processes. Based on the gate-control theory, pain modulation might occur at the level of the dorsal horn.19 Because the brain can process only a limited number of signals at one time, other sensory stimuli at nociceptors might alter pain perception. This theory supports the effectiveness of counterirritants and transcutaneous electrical nerve stimulation (TENS) in pain management. Pain modulation can occur through several other complex processes. The endogenous opiate system consists of endorphins (enkephalins, dynorphins, and β-endorphins) that interact with μ-, δ-, and κ-receptors throughout the CNS to inhibit pain impulses and alter perception. The CNS also includes inhibitory descending pathways from the brain that can attenuate pain transmission in the dorsal horn. Neurotransmitters involved in this descending system include endogenous opioids, serotonin, norepinephrine, γ-aminobutyric acid (GABA), and neurotensin. The perception of pain involves not only nociceptive stimulation but physiologic and emotional input that contributes to the perception of pain. Consequently, cognitive behavioral treatments such as distraction, relaxation, and guided imagery can reduce pain perception by altering pain processing in the cortex.
Peripheral Sensitization, Central Sensitization, and Wind-Up
Under normal conditions, a balance generally exists between excitatory and inhibitory neurotransmission. Changes in this balance can occur both peripherally and centrally, resulting in exaggerated responses and sensitization such as that observed in inflammatory, neuropathic, or functional chronic pain. Pain in these settings might occur spontaneously without any stimulus or might be evoked by a stimulus. Evoked pain might arise from a stimulus that normally does not cause pain (allodynia) such as a light touch in neuropathic pain. Hyperalgesia, an exaggerated and/or prolonged pain response to a stimulus that normally causes pain, can also occur as a result of increased sensitivity in the CNS.
During normal pain transmission, the AMPA receptors are activated, but the N-methyl-D-aspartate (NMDA) receptor is blocked by magnesium.16 Repeated nerve depolarization causes release of the magnesium block, allowing the influx of calcium and sodium, and results in excessive excitability and amplification of signals. Continued input from C-fibers and subsequent increases in substance P and glutamate causes the activation of the NMDA receptor, a process referred to as wind-up. Wind-up increases the number and responsiveness of neuron in the dorsal horn irrespective of the input from the periphery. Recruitment of neurons not normally involved in pain transmission or spread occurs, leading to allodynia, hyperalgesia, and spread to uninjured tissues.20 The wind-up phenomenon supports the observation that untreated acute pain can lead to chronic pain and the belief that pain processes are plastic and not static.
CLINICAL PRESENTATION AND DIAGNOSIS
Classification of Pain
Pain has always been described as a symptom. However, recent advances in the understanding of neural mechanisms have demonstrated that unrelieved pain might lead to changes in the nervous system known as neural plasticity. Because these changes reflect a process that influences a physiologic response, pain, particularly chronic pain, might be considered a disease unto itself.
Pain can be divided into two broad categories, acute and chronic pain. Acute pain is also referred to as adaptive pain since it serves to protect the individual from further injury or promote healing.17 However, chronic pain has been called maladaptive, a pathologic function of the nervous system or pain as a disease.
Acute Pain
Acute pain is pain that occurs as a result of injury or surgery and is usually self-limited, subsiding when the injury heals. Untreated acute pain can produce physiologic symptoms including tachypnea, tachycardia, and increased sympathetic nervous system activity, such as pallor, diaphoresis, and pupil dilation. Furthermore, poorly treated pain can cause psychological stress and compromise the immune system due to the release of endogenous corticosteroids. Somatic acute pain arises from injury to skin, bone, joint, muscle, and connective tissue, and it is generally localized to the site of injury. Visceral pain involves injury to nerves on internal organs (e.g., intestines, liver) and can present as diffuse, poorly differentiated, and often referred pain. Acute pain should be treated aggressively, even before the diagnosis is established, except in conditions of head or abdominal injury where pain might assist in the differential diagnosis.
Chronic Pain
Chronic pain persists beyond the expected normal time for healing and serves no useful physiologic purpose. Chronic pain might be nociceptive, inflammatory, neuropathic, or functional in origin; however, all forms share some common characteristics. Chronic pain can be intermittent or persistent, or both. Physiologic responses observed in acute pain are often absent in chronic pain; however, other symptoms might predominate. There are four main effects of chronic pain, and these include: (a) effects on the physical function, (b) psychological changes, (c) social consequences, and (d) societal consequences. Effects of chronic pain on physical function include impaired activities of daily living and sleep disturbances. Psychological components of chronic pain might include depression, anxiety, anger, and loss of self-esteem. As a result of physical and psychological changes, social consequences might ensue, such as changes in relationships with friends and family, intimacy, and isolation. On a societal level, chronic pain contributes to increased health care costs, disability, and lost productivity. Management of chronic pain should be multimoda land might involve cognitive interventions, physical manipulations, pharmacologic agents, surgical intervention, and regional or spinal anesthesia.
Chronic Malignant Pain
Chronic malignant pain is associated with a progressive disease that is usually life-threatening such as cancer, AIDS, progressive neurologic diseases, end-stage organ failure, and dementia.21 The goal is pain alleviation and prevention, often through a systematic and stepwise approach. Tolerance, dependence, and addiction are often not a concern due to the terminal nature of the illness.
Chronic Nonmalignant Pain
Pain not associated with a life-threatening disease and lasting longer than 6 months beyond the healing period is referred to as chronic nonmalignant pain. Pain associated with low back pain, osteoarthritis, previous bone fractures, peripheral vascular disease, genitourinary infection, rheumatoid arthritis, and coronary heart disease is considered nonmalignant. The numerous causes of this type of chronic pain make treatment complex and involves a multidisciplinary approach. Treatment is initially conservative but might involve the use of more potent analgesics including opiates in psychologically healthy patients.22
Neuropathic Pain
Neuropathic pain is considered to be a type of chronic nonmalignant pain involving disease of the central and peripheral nervous systems. Neuropathic pain might be broadly categorized as peripheral or central in nature. Examples of neuropathic pain include PHN, which is pain associated with acute herpetic neuralgia or an acute shingles outbreak. Peripheral or polyneuropathic pain is associated with the distal polyneuropathies of diabetes, human immunodeficiency virus (HIV), and chemotherapeutic agents. Types of central pain include central stroke pain, trigeminal neuralgia, and a complex of syndromes known as complex regional pain syndrome (CRPS). CRPS includes both reflex sympathetic dystrophy and causalgia, both of which are neuropathic pain associated with abnormal functioning of the autonomic nervous system. One of the newest categories of neuropathic pain is neuropathic low back pain.
Clinical Presentation and Diagnosis of Pain Management
General
Patients may be in acute distress (acute pain) or have no signs or symptoms of suffering (chronic pain).
Symptoms
Pain is described based on the following characteristics: onset, duration, location, quality, severity, and intensity. Other symptoms may include anxiety, depression, fatigue, anger, fear, and insomnia.
Signs
Acute pain may cause hypertension, tachycardia, diaphoresis, mydriasis, and pallor.
Diagnosis
The patient is the only person who can describe the intensity and quality of their pain. There are no laboratory tests that can diagnose pain.
The symptoms of neuropathic pain are characterized as tingling, burning, shooting, stabbing, electric shock–like quality, or radiating pain. The patient might describe either a constant dull throbbing or burning pain, or an intermittent pain that is stabbing or shooting. Damage to the peripheral nerves might frequently be referred to the body region innervated by those nerves.
Pain Assessment
Effective pain management begins with a thorough and accurate assessment of the patient. Even though pain is a common presenting complaint, lack of regular assessment and reassessment of pain remains a problem and contributes to the undertreatment of pain.23
Pain Assessment Guidelines/Regulations for Specific Practice Settings
Screening for pain should be a part of a routine assessment, and this has led several organizations such as the Veterans Health Administration (VHA) and the American Pain Society (APS) to declare pain as the fifth vital sign. Many states have adopted a bill of rights for patients in pain. In 2001, the Joint Commission on Accreditation of Health Care Organizations (JCAHO) incorporated pain as the fifth vital sign in its accreditation standards.24 According to the JCAHO, patients have a right to appropriate assessment and management of their pain and education regarding their pain. Following initial assessment of pain, reassessment should be done as needed based on medication choice and the clinical situation.
Methods of Pain Assessment
A patient-oriented approach to pain is essential, and methods do not differ greatly from those used in other medical conditions. A comprehensive history (medical, family, and psychological) and physical are necessary to evaluate underlying disease processes for the source of pain and other factors contributing to the pain.20 A thorough assessment of the characteristics of the pain should be completed, including questions about the pain (onset, duration, location, quality, severity, and intensity), pain relief efforts, and efficacy and side effects of current and past treatments for pain. A common mnemonic for pain assessment is PQRST (Palliative/precipitating, Quality, Radiation, Severity, and Time).25 Some clinicians have suggested the addition of U (you) to this mnemonic.26 During the pain interview, the impact of the pain on the patient’s functional status, behavior, and psychological states should also be assessed. Evaluation of psychological status is especially important in patients with chronic pain since depression and affective disorders might be common comorbid conditions. A history of drug and alcohol should be elicited due to the potential for addiction in patients who might require opiates or other pain medications with a potential for abuse. Other conditions, such as renal or hepatic dysfunction, diabetes, and conditions that effect bowel function, can influence therapy choices and goals. A discussion of the patient’s expectations and goals with respect to pain management (level of pain relief, functional status, and quality of life) should also be part of any pain interview.
Pain Assessment Tools
Pain, particularly acute pain, might be accompanied by physiologic signs and symptoms, but there are no reliable objective markers for pain. Many tools have been designed for assessing the severity of pain including rating scales and multidimensional pain assessment tools.
Rating scales provide a simple way to classify the intensity of pain, and should be selected based on the patient’s ability to communicate (Fig. 33–1).27 Numeric scales are widely used and ask patients to rate their pain on a scale of 0 to 10, with 0 indicating no pain and 10 being the worst pain possible. Using this type of scale, 1 to 3 is considered mild pain, 4 to 6 is moderate pain, and 8 to 10 is severe pain. The visual analog scale (VAS) is similar to the numerical scale in that it requires patients to place a mark on a 10-cm line where one end is no pain, and the worst possible pain is on the other end. For patients who have difficulty assigning a number to their pain, a categorical scale might be an option to communicate the intensity of the pain experience. Examples of this include a simple descriptive list of words and the Wong-Baker FACES of Pain Rating Scale.28
Multidimensional assessment tools obtain information about the pain and impact on quality of life, but are often more time-consuming to complete. Examples of these types of tools include the Initial Pain Assessment Tool, Brief Pain Inventory, McGill Pain Questionnaire, the Neuropathic Pain Scale, and the Oswestry Disability Index.29–33
FIGURE 33–1. Pain rating scales. (From Ref. 27.)
Pain Assessment in Challenging Populations
Children. Pain interviews can be conducted with children as young as 3 or 4 years of age; however, communication might be limited by vocabulary.34 Terms familiar to children such as hurt, owie, or boo boo might be used to describe pain. The VAS is best used with children older than 7 years. Other scales based on numbers of objects (e.g., pokers chips), increasing color intensity, or faces of pain might be helpful for children between 4 and 7 years of age. In children younger than 3 to 4 years, behavioral or physiologic measures, such as pulse or respiratory rate, might be more appropriate. Pain assessment in newborns and infants relies on behavioral observation for such clues as vocalizations (crying and fussing), facial expressions, body movements (flailing of limbs and pulling legs in), withdrawal, and change in eating and sleeping habits.35 Preschool children experiencing pain might become clingy, lose motor and verbal skills, and start to deny pain because treatment might be linked to discomfort or punishment. School-age children might exhibit aggressiveness, nightmares, anxiety, and withdrawal when in pain, while adolescents might respond to pain with oppositional behavior and depression.
Elderly. Most of the previously discussed pain scales can be used in older persons who are cognitively intact or with mild dementia. The pain thermometer and FACES of pain have been studied in older persons. In persons with moderate-to-severe dementia or those who are nonverbal, observation of pain behaviors, such as guarding or grimacing, provides an alternative for pain assessment. The Pain Assessment in Advanced Dementia (PAINAD) tool might be used to quantify signs of pain and involves observing the older adult for 15 minutes for breathing, negative vocalizations, facial expression, body language, and consolability.36 Regardless of which pain assessment tool is used, the practitioner should first determine if the patient understands the concept of scale to ensure reliability of the instrument.
Patient Encounter 1, Part 1
HPI: BA is a 58-year-old male recently diagnosed with lung cancer. Following surgery he was placed on morphine patient-controlled analgesia (PCA). He has been using 80 mg of morphine/24 hours with adequate pain control.
PMH: Hypertension × 18 years
FH: Noncontributory
SH: Lives with wife; has four grown children; smoked two packs of cigarettes per day × 40 years (quit with diagnosis of lung cancer)
Meds: Hydrochlorothiazide 25 mg every day
Pain assessment: Patient rates pain as 8 on a scale of 1 to 10.
The physician would like to convert him to a combination preparation of oxycodone and APAP. What dosing regimen would you suggest?
Six months later, BA’s pain is controlled with the escalating doses of the combination product; however, he has exceeded the maximum daily dose of APAP. What would you suggest at this time?
TREATMENT
General Approach to Treatment
Effective treatment involves an evaluation of the cause, duration and intensity of the pain and selection of an appropriate treatment modality for the pain situation. Depending on the type of pain, treatment might involve pharmacologic and nonpharmacologic therapy or both. General principles for the pharmacologic management of pain are listed in the section: Patient Care and Monitoring. Two common approaches to the selection of treatment are based on severity of pain and the mechanism responsible for the pain (Fig. 33–2). Clinical practice guidelines for pain management are available from the APS, the Agency for Health care Research and Quality (AHRQ), the American Geriatrics Society (AGS), and the American Society of Anesthesiologists (ASA).
Selection of Agent Based on Severity of Pain
Whenever possible, the least potent, oral analgesic should be selected. Guidelines for the selection of therapeutic agents based on pain intensity are derived from the World Health Organization (WHO) analgesic ladder for the management of cancer pain (Table 33–1).37 Mild-to-moderate pain is generally treated with nonopioid analgesics. Combinations of medium-potency opioids and acetaminophen (APAP) or nonsteroidal anti-inflammatory drugs (NSAIDs) are often used for moderate pain. Potent opioids are recommended for severe pain. Throughout this progression, adjuvant medications are added, as needed, to manage side effects and to augment analgesia. While these guidelines can be useful for initial therapy, the clinical situation (type of pain), cost and pharmacokinetic profile of available drugs, and patient-specific factors (age, concomitant illnesses, previous response, and other medications) must also be considered. Pain medications might also be used in the absence of pain in anticipation of a painful event such as surgery to minimize peripheral and central sensitization.
Table 33–1 Selection of Analgesics Based on Intensity of Pain
FIGURE 33–2. Pain algorithm.
Mechanistic Approach to Therapy
Current analgesic therapy is aimed at controlling or blunting pain symptoms. However, diverse mechanisms contributing to the various types of pain continue to be further elucidated. An understanding of these new mechanisms of pain transmission might lead to improvement in pain management, as pharmacologic management of pain becomes more mechanism-specific. Use of NSAIDs for inflammatory types of pain is an example of a mechanistic approach. Since several mechanisms of pain often coexist, a polypharmacy approach seems rational to target each mechanism.
Two current foci in pain management are to identify the mechanisms that are responsible for pain hypersensitivity and to prevent this initial hypersensitivity. Therefore, the goal of pain therapy is to reduce peripheral sensitization and subsequent central stimulation and amplification associated with wind-up, spread, and central sensitization.17
Nonpharmacologic Therapy
Nonpharmacologic therapies (psychological interventions and physical therapy) might be used in both acute and chronic pain. Psychological interventions can reduce pain as well as the anxiety, depression, fear, and anger associated with pain. Psychological interventions helpful in management of acute pain are imagery (picturing oneself in a safe, peaceful place) and distraction (listening to music or focusing on breathing). Chronic pain patients might benefit from relaxation, biofeedback, cognitive behavioral therapy, psychotherapy, support groups, and spiritual counseling. Biofeedback teaches patients to control physiological responses to pain and has been effective in headache and chronic low back pain. Cognitive therapy encourages patients to monitor their perceptions of pain, reducing stress and negativism. Psychotherapy is very useful for patients with chronic pain; it can also assist in treatment of psychiatric comorbidities and help patients to deal with terminal illness.38 The patient should be educated about what to expect regarding pain and its treatment, whether pain is acute pain (i.e., preoperative explanations of expected postsurgic pain) or chronic (i.e., patient and family education in hospice care).
Physical therapy is an essential part of many types of pain situations. Treatment modalities include heat, cold, water, ultrasound therapy, TENS, massage, and therapeutic exercise. Heat and cold therapy are utilized in a variety of musculoskeletal conditions (muscle spasms, low back pain, fibromyalgia, sprains, and strains). Heating modalities include local hot packs, paraffin wrap, hydrotherapy, and deep-heating methods (ultrasound). Cold treatments might be delivered via cold packs, ice massage, cold water immersion, or coolant sprays. TENS therapy is based on the theory that electrical stimulation of a nerve in a particular area can block pain impulses originating from that area. TENS is also believed to release endogenous endorphins and enkephalins. Massage therapy is used to relieve muscle tension and stiffness and is also felt to increase endogenous endorphins. Therapeutic exercise improves not only strength, endurance, and range of motion, but also provides cardiovascular, psychological, and other health benefits.
Pharmacologic Therapy
Nonopioid Analgesics
Acetaminophen
APAP, an analgesic and antipyretic, is often selected as initial therapy for mild-to-moderate pain and is considered first-line in several pain situations such as low back pain and osteoarthritis.39Mechanistically, APAP is believed to inhibit prostaglandin synthesis in the CNS and block pain impulses in the periphery. APAP is well tolerated at usual doses and has few clinically significant drug interactions except causing increased hypoprothrombinemic response to warfarin in patients receiving APAP doses of more than 2,000 mg per day. The maximum recommended dose for patients with normal renal and hepatic function is 4,000 mg per day. Hepatotoxicity has been reported with excessive use and overdose, and the risk of this adverse effect increases in those with hepatitis or chronic alcohol use, as well as those who binge drink or are in a fasting state. Regular chronic use of APAP has been associated with chronic renal failure, but reports are conflicting. For these reasons, the maximum dose should be reduced by 50% to 75% in patients with renal dysfunction or hepatic disease and in those who engage in excessive alcohol use.
Aspirin and Other Salicylates
Aspirin, nonacetylated salicylates, and other NSAIDs have analgesic, antipyretic, and anti-inflammatory actions. These agents inhibit cyclo-oxygenase (COX-1 and COX-2) enzymes, thereby preventing prostaglandin synthesis, which results in reduced nociceptor sensitization and an increased pain threshold. NSAIDs are the preferred agents for mild-to-moderate pain in situations that are mediated by prostaglandins (rheumatoid arthritis, menstrual cramps, and postsurgical pain) and in the management of pain from bony metastasis, but they are of minimal use in neuropathic pain.
Aspirin is effective for mild-to-moderate pain; however, the risk of GI irritation and bleeding limits frequent use of this drug for pain management. Direct effects of aspirin on the GI mucosa and irreversible platelet inhibition contribute to this risk, which can occur even at low doses. Hypersensitivity reactions are also possible and might occur in 25% of patients with coexsiting asthma, nasal polyps, or chronic urticaria. Of additional concern is the potential for cross-sensitivity of other NSAIDs in this group of patients. Nonacetylated salicylates (choline magnesium salicylate and sodium salicylate) have a reduced risk of GI effects and platelet inhibition and might be used in aspirin-sensitive patients. Diflunisal, a salicylic acid derivative, is associated with fewer GI complaints compared to aspirin, but platelet inhibition does increase the risk of GI bleeding.
Nonsteroidal Anti-inflammatory Drugs
NSAIDs provide analgesia equal to or better than that of aspirin or APAP combined with codeine, and they are very effective for inflammatory pain and pain associated with bone metastasis.18 These agents are classified by their chemical structures (fenamates, acetic acids, propionic acids, pyranocarboxylic acids, pyrrolizine carboxylic acids, and COX-2 inhibitors). While only some members of this class have approval for treatment of pain, it is likely that all of them have similar analgesic effects. All members of this class appear to be equally effective, but there is great intrapatient variability in response. After an adequate trial of 2 to 3 weeks with a particular oral agent, it is reasonable to switch to another member of the class. Ketorolac is available in parenteral and oral dosage forms; unlike other NSAIDs, its duration of use is limited to 5 days. NSAIDs demonstrate a flat-dose response curve, with higher doses producing no greater efficacy than moderate doses but resulting in an increased incidence of adverse effects (GI irritation, hepatic dysfunction, renal insufficiency, platelet inhibition, sodium retention, and CNS dysfunction).
Patients at increased risk of NSAID-induced GI adverse effects (e.g., dyspepsia, peptic ulcer formation, and bleeding) include the elderly, those with peptic ulcer disease, coagulopathy, and patients receiving high doses of concurrent corticosteroids. Nephrotoxicity is more common in the elderly, patients with creatinine clearance values less than 50 mL/min, and those with volume depletion or on diuretic therapy. NSAIDs should be used with caution in patients with reduced cardiac output due to sodium retention and in patients receiving antihypertensives, warfarin, and lithium.
NSAIDs are classified as nonselective (they inhibit COX-1 and COX-2) or selective (inhibit only COX-2) based on degree of COX inhibition. COX-2 inhibition is responsible for anti-inflammatory effects, while COX-1 inhibition contributes to increased GI and renal toxicity associated with nonselective agents. Because the antiplatelet effect of nonselective NSAIDs is reversible, concurrent use might reduce the cardioprotective effect of aspirin due to competitive inhibition of COX-1. For this reason, administration of aspirin prior to the NSAID is recommended.40 The cardiovascular safety of the COX-2 inhibitors has been questioned due to increased risk of myocardial infarction (MI) and stroke noted in several trials.41–43 The FDA Committees on Arthritis and Drug Safety and Risk Management convened in February 2005 to evaluate the published studies and manufacturer information about the cardiovascular adverse events associated with COX-2 inhibitors.44 As a follow-up to the committee’s recommendations, the FDA took regulatory action in April 2005 announcing that the increased risk of cardiovascular events was likely a class effect of NSAIDs. A boxed warning highlighting the potential for increased risk of cardiovascular events and GI bleeding is now required for all prescription nonselective NSAIDs and celecoxib. Stronger warnings about these adverse events are also required on nonprescription NSAIDs. As a result of the data and subsequent events, two members of this class, rofecoxib and valdecoxib, have been withdrawn from the market. Future COX-2 inhibitors and nonselective NSAIDs will likely have to undergo cardiovascular safety studies before receiving FDA approval. When a NSAID is needed in a patient with cardiovascular risk, the benefits of therapy must outweigh the risks, and the lowest effective dose of NSAID is recommended.
Opioid Analgesics
Opioids are considered the agents of choice for the treatment of severe acute pain and moderate-to-severe pain associated with cancer.45 For chronic pain, their use was once highly controversial, however, use of opioids in chronic pain is now gaining acceptance.46 Opioids are classified by their activity at the receptor site, usual pain intensity treated, and duration of action (short- vs. long-acting).
Selection and Dosing
The opioids exert their analgesic efficacy by stimulating opioid receptors (μ, κ, and δ) in the CNS. There is a wide variety of potencies among the opioids, with some used for moderate pain (codeine, hydrocodone, tramadol, and partial agonists) and others reserved for severe pain (morphine and hydromorphone). Pure agonists (morphine) bind to μ-receptors to produce analgesia that increases with dose without a ceiling effect. Pure agonists are divided into three chemical classes, phenanthrenes or morphine-like, phenylpiperidine or meperidine-like, and diphenylheptane or methadone-like. Partial agonists/antagonists (butorphanol, pentazocine, and nalbuphine) partially stimulate the μ-receptor and antagonize the μ-receptors. This activity results in reduced analgesic efficacy with a ceiling dose, reduced side effects at the κ-receptor, psychotomimetic side effects due to K-receptor antagonism, and possible withdrawal symptoms in patients who are dependent on pure agonists.
Patient Encounter 1, Part 2: Converting to Different Drugs and Adjusting Doses
Two years following his diagnosis of lung cancer, BA has been diagnosed as having bone metastases. Pain has been controlled with the following medications: hydromorphone (Dilaudid) 10 mg IV every hour and levorphanol (Levo-Dromoran) 10 mg orally every 4 hours. He is currently receiving hydrochlorothiazide 25 mg daily, senna 2 tablets twice daily, and docusate sodium 100 mg twice daily. As the home care pharmacist, you are asked to convert this patient’s pain medications to a morphine infusion.
Morphine equivalents (based on 10 mg parenteral morphine) (Table 33–2)
Parenteral hydromorphone 1.5 mg is equivalent to 10 mg of parenteral morphine.
Levorphanol 4 mg orally is equivalent to 10 mg of parenteral morphine.
Based on BA’s opioid requirement, recommend an initial infusion rate (in milligrams per hour) of parenteral morphine.
Which adjuvant therapy could be considered for BA?
Recommend a monitoring plan for this patient.
How would you assess pain response?
Selection of the agent and route depend on individual patient-related factors including severity of pain, individual perceptions, weight, age, opioid tolerance, and concomitant disease (renal or hepatic dysfunction). Because pure agonists are pharmacologically similar, choice of agent might be also guided by pharmacokinetic parameters and other drug characteristics. Hepatic impairment can decrease the metabolism of most opioids, particularly methadone, meperidine, pentazocine, and propoxyphene. Furthermore, the clearance of meperidine, propoxyphene, and morphine and their metabolites is reduced in renal dysfunction.
Table 33–2 provides a summary of opiate options, but several drugs warrant further discussion. Normeperidine, the active metabolite of meperidine, can produce tremors, myoclonus, delirium, and seizures. Due to the potential for accumulation of normeperidine, meperidine should not be used in the elderly, those with renal impairment, in patients using patient-controlled analgesia (PCA) devices, or for more than 1 to 2 days of intermittent dosing. Propoxyphene also has an increased risk of seizures and cardiac conduction abnormalities and should be avoided in the elderly. Despite its popularity, propoxyphene has proven to be no more effective than APAP, aspirin, or codeine alone.18 Methadone is unique among the opiates as it has several mechanisms (μ-agonist, NMDA-receptor antagonist, and inhibition of reuptake of serotonin and norepinephrine) that make it an interesting choice for chronic pain. The long-half of methadone (30 hours) permits extended dosing intervals; however, the potential for accumulation with repeated dosing often results in challenging dose conversion. Tramadol is a synthetic opioid with a dual mechanism of action (μ-agonist and inhibition of serotonin and norepinephrine reuptake) and efficacy and safety similar to that of equianalgesic doses of codeine plus APAP. Tramadol has been evaluated in several types of neuropathic pain and might have a role in the treatment of chronic pain. Tramadol is associated with an increased risk of seizures in patients with a seizure disorder, those at risk for seizures, and those taking medications that can lower the seizure threshold. Doses greater than 500 mg have also been associated with seizures. The use of tramadol with other serotonergic drugs (e.g., selective serotonin reuptake inhibitors [SSRI]) might precipitate serotonin syndrome. While originally thought to be nonhabit forming, dependence can occur with tramadol.
Table 33–2 Equianalgesic Doses of Selected Opioids
About 70% of individuals will experience significant analgesia from 10 mg/70 kg of body weight of IV morphine or its equivalent.18 For severe pain in opiate-naive patients, a usual starting dose is 5 to 10 mg of morphine every 4 hours. In the initial stages of severe pain, medication should be given around the clock. Rescue doses should be made available for breakthrough pain in doses equivalent to 10% to 20% of the total daily opioid requirement and administered every 2 to 6 hours if needed. Alternatively 1/6 of the total daily dose or 1/3 of the 12-hourly dose might be used. Scheduled doses should be titrated based on the degree of pain. One method involves adjustment of the maintenance dose based on the total 24-hour rescue dose requirement. Alternatively, utilizing dose escalation, doses could be increased by 50% to 100% or 30% to 50% of the current dose, for those in severe and moderate pain, respectively. Once pain relief is achieved, and if treatment is necessary for more than a few days, conversion to a controlled-release or long-acting opioid should be made with an equal amount of agent. Several sustained-release products are available containing morphine, oxycodone, and fentanyl. Some clinicians will reduce the total daily dose of the long-acting dosage form by 25% when initiating a sustained-release product to reduce the likelihood of oversedation. The dose of a pure agonist is limited only by tolerability to side effects. Tolerance might develop to analgesic effects, necessitating increasing doses to achieve the same level of pain relief. Physical dependence will also occur with long-term use of opioids. However, addiction or psychological dependence is unlikely in legitimate pain patients unless there are predisposing risk factors. Pain patients who are undertreated might appear to be drug-seeking (pseudoaddiction), however effective pain management resolves the behaviors. When opioids are used for chronic pain, use of informed consent for chronic opioid therapy, medication management agreements, or pain contracts might be appropriate to monitor the use (prescribing and dispensing) of controlled substances.
Opioids are administered by a variety of routes, including oral (tablet and liquid), sublingual, rectal, transdermal, transmucosal, IV, subcutaneous, and intraspinal. While the oral and transdermal routes are most common, the method of administration is based on patient needs (severity of pain) and characteristics (swallowing difficulty and preference). Oral opioids have an onset of effect of 45 minutes, so IV or subcutaneous administration might be preferred if more rapid relief is desired. Intramuscular (IM) injections are not recommended because of pain at the injection site and wide fluctuations in drug absorption and peak plasma concentrations achieved. More invasive routes of administration such as PCA and intraspinal (epidural and intrathecal) are primarily used postoperatively, but might also be used in refractory chronic pain situations. PCA delivers a self-administered dose via an infusion pump with a preprogrammed dose, minimum dosing interval, and a maximum hourly dose. Morphine, fentanyl, and hydromorphone are commonly administered via PCA pumps by the IV route, but less frequently by the subcutaneous or epidural route.
Epidural analgesia is frequently used for lower extremity procedures and pain (e.g., knee surgery, labor pain, and some abdominal procedures). Intermittent bolus or continuous infusion of preservative-free opioids (morphine, hydromorphone, or fentanyl) and local anesthetics (bupi-vacaine) might be used for epidural analgesia. Opiates given by this route might cause pruritus that is relieved by naloxone. Adverse effects including respiratory depression, hypotension, and urinary retention might occur. When epidural routes are used in narcotic-dependent patients, systemic analgesics must also be used to prevent withdrawal since the opioid is not absorbed and remains in the epidural space. Doses of opioids used in epidural analgesia are 10 times less than IV doses, and intrathecal doses are 10 times less than epidural doses (i.e., 10 mg of IV morphine is equivalent to 1 mg epidural morphine and 0.1 mg of intrathecally administered morphine).45
Combination Analgesics
Combinations of opioids and nonopioids often result in enhanced analgesia and lower dose of each. Combination analgesics are frequently used in moderate pain. However, in severe pain, the nonopioid component reaches maximum dosage, and thus the usefulness of nonopioids in this situation is limited. Additionally, the combination products are short acting and often not suitable for chronic therapy. Single agents offer greater dosing flexibility than combination products.
Opioid Allergy
True narcotic allergies are rare and should not be confused with pruritus associated with opiate use. Cross-sensitivity between morphine-like, meperidine-like, and methadone-like agents is unlikely. Therefore, when an individual is allergic to one drug in a chemical class of opioids, it is reasonable to select an agent in another chemical class. For the purpose of drug selection in patients with allergies, mixed agonists/antagonists should be treated as morphine-like agents.
Tapering of Opioids
Tapering of opioids might be necessary once the painful situation has resolved in patients receiving doses greater than 160 mg/day of oral morphine (or the equivalent) or in those with prolonged opioid use. In these situations the dose should be reduced by 15% to 20% each day to avoid withdrawal symptoms.
Managing Opioid Side Effects and Drug Interactions
Side effects common to all opioids include sedation, hallucinations, constipation, nausea and vomiting, urinary retention, myoclonus, and respiratory depression. Table 33–3 shows side-effect management strategies. In terms of medication management, the most frequent are sedation, nausea, and constipation. Sedation and nausea are common when initiating therapy and when increasing doses. Nausea can be prevented with a centrally acting antiemetic. Sedation usually improves with continued therapy but might become intractable at high doses, and stimulants, such as methylphenidate might be needed. Respiratory depression is a serious adverse effect, and usually occurs after acute administration in opioid-naive patients. Tolerance to respiratory depression develops rapidly with repeated doses, and respiratory depression is rarely a clinically significant problem in pain patients even those with respiratory impairment. Constipation is a significant adverse effect to which tolerance does develop, and prophylaxis with stimulant laxatives (e.g., senna or bisacodyl) and stool softeners, such as docusate, is recommended.
Codeine, hydrocodone, morphine, methadone, and oxycodone are substrates of the cytochrome P450 (CYP) enzyme—CYP2D6.47 Inhibition of CYP2D6 results in decreased analgesia of codeine and hydrocodone due to decreased conversion to the active metabolites (e.g., morphine and hydromorphone, respectively) and increased effects of morphine, methadone, and oxycodone. Methadone is also a substrate of CYP3A4, and its metabolism is increased by phenytoin and decreased by cimetidine. CNS depressants might potentiate the sedative effects of opiates.
Opioid Rotation
Opioid rotation is the switch from one opioid to another to achieve a better balance between analgesia and treatment limiting adverse effects. This practice is often used when escalating doses (greater than 1 gram of morphine/day) become ineffective. In some settings, opioid rotation is utilized routinely to prevent the development of analgesic tolerance.48
Equianalgesic Dosing of Opioid Analgesics
Conversion from one dosage form to another or from one opioid to another might be necessary in situations such as ineffective pain control, emergence of side effects, change in patient status, and in formulary restrictions. Equianalgesic doses should be used when converting from one opioid to another. Clinicians should be familiar with the equianalgesic dosing and conversion strategies to avoid analgesic failure. Equianalgesic tables serve as a guide for selection of the dosage of the new opioid, but have limitations as they are often based on single-dose studies and clinical observations.49 Opioid potency is compared using a reference standard of 10 mg of parenteral morphine. Switching from one dosage form to another of the same opioid (i.e., IV to oral) is relatively simple. The current total daily dose is calculated and the total of the new dosage form is determined using a ratio of the equianalgesic doses. This result is then adjusted based on the usual dosing frequency of the new form. When converting to a sustained-release form of the same opioid, dosage may be reduced by 25% to avoid initial sedation; however, the specific product literature should also be consulted.
Table 33–3 Managing Opioid Side Effects
The first step in an opioid rotation is to calculate the patient’s total daily dose of opioid based on the regularly scheduled dose and the total amount of rescue dose needed in 24 hours. This total is then converted to morphine-dosing equivalents using equianalgesic doses (Table 33–2). The total daily morphine dose is then used to calculate the daily dose of the new opioid using dosing equivalents from an equianalgesic table. Because cross-tolerance may not be complete between opioids, some references suggest that the calculated equianalgesic dose be reduced by 25% to 50%.49 If the opioid switch is due to uncontrolled pain, a dosage reduction may not be needed. The calculated equianalgesic dose may need to be reduced more in the medically frail and when converting to methadone.50,51 Methadone appears to be much more potent than once believed, and morphine to methadone ratios vary according to the total dose of morphine taken at the time of making the conversion to methadone (Table 33–4).52,53Conversion to methadone is a complex process, and several different strategies have been proposed including a switch of the entire dose in one day or a gradual conversion over 3 days.
Adjuvant Agents for Chronic Pain
The role of NSAIDs and opioids in chronic nonmalignant pain has been discussed; however, a review of adjuvant agents for chronic pain, particularly neuropathic pain, is warranted. Adjuvant analgesics are drugs that have indications other than pain but are useful as monotherapy or in combination with nonopioids and opioids. Common adjuvants include antiepileptic drugs (AEDs), antidepressants, antiarrhythmic drugs, local anesthetics, topical agents (e.g., capsaicin), and a variety of other drugs (e.g., NMDA antagonists, clonidine, and muscle relaxants).
There is little consensus on the optimal management of neuropathic pain, because much of the evidence for treatment effectiveness consists of anecdotal reports or poorly designed trials. Published guidelines have been suggested for the general management of neuropathic pain.54 Suggestions for first-line therapy include gabapentin or pregabalin, transdermal lidocaine, or tricyclic antidepressants (TCAs) (Table 33–5).54–58 Newer antidepressants, such as the SSRIs, have fewer side effects but appear to be less effective than the TCAs for neuropathic pain. However, serotonin-norepi-nephrine reuptake inhibitors (SNRIs), (e.g., duloxetine and venlafaxine) have been used successfully for painful DPN. A stepwise approach is suggested for managing the patient with neuropathic pain beginning with the least-invasive effective therapeutic choice and proceeding to the rational use of multiple drug regimens. To guide choice of pharmacologic agents, patients might be identified as candidates for AEDs, TCAs, or opioids based on the presence of peripheral or central nerve pain and description of symptoms (Fig. 33–2). Choice of agent might also depend on dosing frequency and comorbidities. Data on combination therapy are lacking, and the use of combined treatment is empirical based on additive therapeutic benefit. Scheduled medication regimens instead of “as-needed” dosing should be employed when treating chronic pain, and the effectiveness of therapy should be reassessed regularly. If patients are managed on a multiple drug regimen and changes are indicated, changing only one drug at a time is suggested. Topical agents (e.g., capsaicin) might be added to a regimen to reduce the oral medication load, particularly if adverse effects are a problem or if pain is not relieved.
Table 33–4 Methadone Dose Conversions
Table 33–5 Selected Adjuvant Analgesics and Suggested Dosing
Complementary and Alternative Medicine
Complementary and alternative medicine (CAM) is a term used to encompass a variety of therapies (e.g., acupuncture, chiropractic, botanical and nonbotanical dietary supplements, and homeopathy). Painful conditions are among the most common reasons individuals seek relief from CAM. In a recent survey, neck pain, joint pain, arthritis, and headache were among the top ten reasons for use of CAM, and low back pain ranked the number one reason for CAM therapies. Of the CAM therapies, chiropractic and acupuncture are the most accepted and utilized modalities. A variety of dietary supplements have been suggested for painful conditions such as S-adenosylmethionine (SAM-e), ginger, fish oil, feverfew, γ-linoleic acid, glucosamine, and chondroitin. Of these, glucosamine and chondroitin are the most popular and have the most evidence supporting their efficacy. Glucosamine in doses of 1,500 mg/day has been shown to be effective in reducing pain of osteoarthritis by fostering repair of cartilage, and it is recommended by the Osteoarthritis Research Society International (OARSI).59
OUTCOME EVALUATION
Individualize the treatment goals at the beginning of treatment. Utilize information obtained during the pain interview to create goals that are consistent with the patient’s expectations. Prevention, reduction, or elimination of pain are important goals for treatment of acute pain. With chronic pain, elimination of pain might not be possible, and goals might focus on improvement or maintenance of functional capacity and quality of life. Thus, for example, pain goals might include “pain scale less than three,” or “be able to play a game with grandchildren,” or “be able to knit again.” Assess patients periodically, depending on the method of analgesia and pain condition, for achievement of pain goals. Evaluate the patient for the presence of adverse drug reactions, drug allergies, and drug interactions.
Patient Care and Monitoring
1. Identify the source of pain.
2. Assess the level of pain using a pain intensity scale.
3. Base the initial choice of analgesic on the severity and type of pain, as well as on the patient’s medical condition and concurrent medications.
4. Use the least potent oral analgesic that provides adequate pain relief and causes the fewest side effects.
5. Titrate the dose to one that achieves an adequate level of pain control.
6. Use a dosing schedule versus as-needed dosing.
7. Assess the patient for analgesic effectiveness and for side effects at each visit or more frequently, depending on the acuity of the patient’s condition.
8. Avoid excessive sedation.
9. Adjust the route of administration if the patient is unable to take oral medications.
10. Use equianalgesic doses as a guide when switching opioids.
Abbreviations Introduced in This Chapter
Self-assessment questions and answers are available at http://www.mhpharmacotherapy.com/pp.html.
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