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This continuing education article was written directly from the transcripts of the continuing education symposium, "Chronic Pain and Opioids: The Rise of Pharmaceutical Care,"that was presented at the American Pharmacists Association meeting on Sunday, April 3, 2005, in Orlando, Fla. The clinical application of equianalgesic tables when rotating opioids is also reviewed. Portions of the information included in this article are represented in the published literature, while the remainder reflects opinions of the presenting faculty, based on their clinical experience.
"Pain is whatever the experiencing person says it is, existing whenever he says it does."1 The International Association of the Study of Pain defines pain as "an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage."2 Objective parameters to diagnose and measure pain do not exist. Thus, pain is subjective and must be based on the individual's perception of, reaction to, and tolerance to pain.
Approximately 50 million Americans?1 in 5 people?suffer from pain. Unfortunately, this number is expected to rise over the next 2 decades. The majority of chronic pain sufferers have been living with their pain for over 5 years. Annual health care costs associated with pain average $100 billion, and pain contributes to 50 million lost work days. Chronic pain causes more disability than cancer and heart disease combined.3 A joint statement from 21 health organizations remarked, "Undertreatment of pain is a serious problem.... Effective pain management is an integral and important aspect of quality medical care, and pain should be treated aggressively."4
Consequences of Unrelieved Pain
Minority, female, cognitively impaired, and geriatric patients are significantly less likely to receive appropriate pain medication and, consequently, more likely to suffer from inadequate pain relief.5,6 Unrelieved pain affects not only the quality of life and economic security of the person with pain, but also his or her family.7 Table 1 summarizes the negative consequences of unrelieved pain.8
Characteristics of Acute and Chronic Pain
An understanding of the pathophysiology of pain is required to adequately control pain. Nociception refers to the process by which information about tissue damage is conveyed to the central nervous system.9 Tissue damage stimulates the ascending transmission of pain through the spinal cord to the brain. The brain modulates pain impulses by the release of endogenous opioids, such as endorphin, that descend to inhibit pain. These opioids bind to mu, kappa, or delta receptors to decrease transmission of the pain. Exogenous opioids work at the same mu, kappa, or delta and/or other opioid receptors. Continuous activation of N-methyl-D-aspartate (NMDA) receptors can decrease mu receptors' response to opioids.3,9,10
Acute pain is a normal response after tissue injury and typically subsides once healing has occurred.11 Chronic pain is defined as "pain that persists for longer than the expected time frame for healing or pain associated with progressive, nonmalignant disease."7 Table 2 summarizes similarities and differences between acute and chronic non-cancer-related pain characteristics.7 Chronic nonmalignant pain will be the focus of this continuing education article.
Pain is subjective; therefore, a comprehensive assessment of the pain?ie, the patient's perception of pain, emotional state and somatic preoccupation, functional status at home and at work, and use of analgesic medications? is vital.12 The goals of chronic pain therapy are to decrease pain, increase function, and improve overall quality of life.
Treatment of Chronic Pain
Both nonpharmacologic and pharmacologic treatment strategies are effective in achieving adequate pain relief when used appropriately. Nonpharmacologic treatment options include exercise, acupuncture, massage, transcutaneous electrical nerve stimulation, hydrotherapy, manipulation, guided feedback, hypnotherapy, biofeedback, and treatment of concomitant mood disorders. Certain patients may require the addition of pharmacologic treatment to achieve adequate pain relief.
Acetaminophen, nonsteroidal antiinflammatory drugs (NSAIDs)?including cyclooxygenase type 2 (COX-2) selective agents?muscle relaxants, anticonvulsants, antidepressants, stimulants, sleeping pills, sleep medications, anxiolytics, glucocorticoids, anesthetics, topical analgesics, and opioids may help in adequately controlling chronic pain.
The World Health Organization's (WHO) 3-Step Analgesic Ladder (Figure 1) supports opioids as the cornerstone of analgesic therapy for patients with moderate-to-severe cancer pain.13,14 In clinical practice, the WHO Ladder is commonly extrapolated for patients with non-cancer-related pain.
Numerous barriers to effective pain management with opioid analgesics have been identified. Failure to routinely assess pain and pain relief is the most common reason for unrelieved pain. The Joint Commission on Accreditation of Healthcare Organizations recognizes pain as the fifth vital sign and encourages routine assessment.15 Health-provider barriers include misunderstanding of the pathophysiology of pain, lack of knowledge of opioid analgesic pharmacotherapy, lack of accountability of pain control among health care providers, insufficient supplies of opioids in pharmacies, and legal and regulatory issues governing opioid use and abuse. Patients often underreport pain for fear of addiction, fear of disappointing or annoying friends and family, and to avoid adverse drug events (ADEs).3,4,16-20
Common Opioid ADEs
Recall that exogenous opioids bind to certain opiate receptors in the brain and spinal cord to inhibit the transmission of pain. Activation of these receptors also causes the common ADEs associated with opioid analgesics (Table 3).21-32
It is believed by many that common ADEs of opioids are allergic reactions. A true opioid allergy is rare (<1%), however, and is a reaction in which the body's immune system responds in an overstated way (skin rash, facial swelling, or asthma) to a foreign substance. In the case of a true opioid allergy, the offending opioid should be discontinued and replaced with another opioid from a different analogue class. The theory is to change the chemical structure enough to avoid antibody recognition. Cross-reactivity to another analogue class is rare (Table 4).33-37
Advantages of Long-Acting Opioids
Patients with continuous or frequent pain should be given a fixed scheduled dose of a long-acting opioid to prevent the pain from recurring and to provide continuous relief.22
Long-acting opioids may be more favorable than short-acting opioids for the following reasons38,39:
Choice of long-acting opioid may be limited by renal and hepatic function, however. Metabolites or active drug may accumulate in the presence of renal dysfunction (Table 5) and hepatic dysfunction (Table 6).
Route of Administration
Long-acting agents are available in a variety of delivery systems (Table 7).40 Oral administration is the most common and preferred route by patients. Most oral formulations last less than 24 hours and require multiple daily dosing. If the oral route is not feasible, noninvasive routes such as transdermal or rectal are alternatives. Transdermal delivery allows for enhanced compliance (application usually every 72 hours for fentanyl, although every-48-hour changes are acceptable if required). Rectal administration is not acceptable to many patients. Invasive parenteral routes are reserved for later use. Intramuscular administration of pain medications is not recommended, as this route of administration is painful, yields wide fluctuation in absorption, has up to a 60-minute lag time for analgesic effect, has a rapid falloff, and may cause sterile abscesses and fibrosis of muscle and soft tissue.5,41
Morphine is the gold standard to which all other opioids are compared. Several oral extended-release formulations are available. Controlled-release (CR) morphine sulfate may be administered every 8 to 12 hours.42 Sustained-release (SR) morphine sulfate may be administered every 12 to 24 hours.43,44 CR or SR morphine formulations should not be crushed, as the inherent release property is obliterated, and the patient receives the equivalent of an immediate-acting morphine dose. A sprinkle-dose formulation of morphine sulfate once daily is now available.45 The capsules can be opened and sprinkled on soft food in patients who have difficulty swallowing or who require administration via nasogastric, percutaneous esophageal gastric, or jejunal tubes. Morphine extended-release products are not approved for use in children. Due to morphine's histamine-releasing activity, it may cause more nausea and pruritus than other opioids.
Oxycodone may cause less nausea and pruritus than morphine. It is also more potent than morphine. To prevent overdose especially in opioidna?ve patients, oxycodone CR should not be crushed.46 Oxycodone CR is not FDA-approved for use in children.
Hydromorphone is approximately 5 to 10 times more potent than morphine. Hydromorphone CR tablets are now available and should not be crushed.47 Hydromorphone CR is not FDA-approved for use in children.
Recall that NMDA receptors can decrease mu receptors'response to opioids. Methadone is an mu-receptor agonist and a NMDA-receptor antagonist. Therefore, it may be especially useful during opioid rotation. The concept of opioid rotation is discussed below. Methadone tablets may be crushed, because methadone exhibits long-acting properties due to its long half-life (not drug formulation). An oral solution is also available. Methadone is an alternative in patients with true morphine allergy; it is inexpensive; it does not require renal dose adjustment; it is relatively safe in stable, chronic liver disease; and it may be given once or twice daily. Methadone's unique properties include high oral bioavailability; long, highly variable half-life (up to 190 hours); and high lipophilicity (creates a depot effect by slowing releasing of drug from the tissue into the bloodstream). These unique properties increase the risk of delayed toxicity such as sedation, respiratory depression, and (rarely) coma. Paradoxically, when converting to methadone, higher doses of the chronically taken opioid will result in a relatively more potent methadone response. Equianalgesic tables fail to consider these unique properties of methadone, and dose conversions based on these ratios may result in drastic overdose. When converting to methadone, some references recommend reducing the calculated equianalgesic dose of methadone by 75% to 90% to achieve a well-tolerated and efficacious conversion (Table 8).41 Other sources recommend more accurately dosing in a triphasic fashion such that the conversion ratio changes as the total daily dose of morphine (or its equivalent) increases. For example, when doses of morphine are low (<90 mg/day), the ratio is approximately 4:1 (morphine:methadone). When doses of morphine are high (>300 mg/day), the ratio of oral morphine to oral methadone approaches 12:1. For doses in the middle, a ratio of 8:1 has been studied.52 Methadone may be used in children.
Fentanyl Transdermal System
A fentanyl transdermal system (FTS) is comprised of a protective liner (removed prior to application) and 4 functional layers53:
Cutting this patch renders the system unusable. Generic FTS has a protective liner (removed prior to application) and 2 functional layers54:
Some generic transdermal fentanyl patches do not have a rate-controlling membrane. These patches are a matrixtype system, unlike the compartmental delivery system seen with the Duragesic Transdermal System and similar mechanically and generically equivalent alternatives. In the case of the matrix system, drug absorption is likely more dependent on patient specific characteristics (skin thickness). Cutting this patch may lead to misuse. Both FTSs should be disposed of properly. An FTS may be used in children older than 2 years of age.
An FTS should be reserved for those patients with chronic, stable pain and analgesic needs whose pain cannot be maintained on oral opioids, because the patient is unable to swallow, has a dysfunctional gastrointestinal tract, or is intolerant of other opioids due to allergy or ADEs.53,54 Consideration of dosage, initiation, dose adjustments, and discontinuation of an FTS requires knowledge of the drug delivery system.
Dose Calculation and Conversion to Transdermal Fentanyl53,54
Discontinuation of Transdermal Fentanyl53,54
In summary, long-acting opioids may increase vitality, social functioning, and mental health by providing extended periods of pain relief and fewer ADEs, compared with short-acting opioids.39 Dosing and product selection must be patient-specific. No single medication is perfect for every patient, and some patients may require the use of 2 long-acting opioids.56 Evaluation of treatment outcomes associated with opioid analgesics in chronic pain may be summarized by the 4 As: analgesia, activities of daily living, ADEs, and aberrant drug-related behaviors.57
Inconsistent use of terms related to pain often results in misunderstandings between regulators, health care providers, patients, and the general public regarding the use of opioids for the treatment of pain.58 The establishment of uniform definitions promotes enhanced patient care in patients receiving opioid therapy. It is vital to recognize that physical dependence, tolerance, cross-tolerance, addiction, and pseudoaddiction are all distinct terms.
Physical dependence is defined as "a state of adaptation that is manifested by a drug-class-specific withdrawal syndrome that can be produced by abrupt cessation, rapid dose reduction, decreasing blood level of the drugs, and/or administration of an antagonist."58 Withdrawal symptoms include irritability, chills, nausea, vomiting, diarrhea, abdominal pain, sweating, runny nose, and insomnia. Withdrawal symptoms are not evidence of addiction?they also occur with many nonnarcotic medications (antihypertensives and antidepressants). These symptoms do not occur if the patient continues to take the opioid (avoids abstinence). Physical dependence is a pharmacologic property of the opioid and is common in patients receiving opioid therapy >5 days.5
"Tolerance is a state of adaptation in which exposure to a drug induces changes that result in a diminution of 1 or more of the drug's effects over time."58 Patients with tolerance to opioid therapy require higher than normal doses to achieve the same level of analgesic effect. Tolerance to pain relief is uncommon. Rapid increases in pain or in opioid dose may represent disease progression and not tolerance. Tolerance can also develop to common opioid ADEs. When tolerance develops to a particular opioid, cross-tolerance to other opioids concomitantly develops, although such tolerance may be incomplete.
Cross-tolerance may be thought of as the ability of one drug to suppress the manifestations of physical withdrawal produced by another drug and to maintain the physically dependent state. Caution must be used when switching to an alternative opioid drug; this is also termed opioid rotation or sequential opioid trials.41,59 When rotating opioids, "the degree of tolerance to opioid effects, both analgesic and nonanalgesic, does not fully transfer to the new drug, leading to a greater potency of the new drug than expected."41 Equianalgesic tables do not take into consideration cross-tolerance (Table 8). Thus, it is commonly recommended to decrease the dose of the new opioid by 30% to 50% when initiating a different opioid.41 When keeping the same opioid, but converting to a different route, adjustments for cross-tolerance do not have to be made.
Although physical dependence is common, addiction is rare in patients treated with prolonged opioid therapy.57,60 Addiction is defined as "a maladaptive pattern of substance use leading to clinically significant impairment or distress."61 Addiction is a psychological property of the patient. Addictive behaviors are psychological in nature and include a dysfunctional and compulsive pattern of use in which craving, obtaining, and using a drug constitute the principal focus of the user's life; in addition, use is continued despite harm. Addiction is diagnosed by the observation of aberrant drug-related behavior (Table 10).56,57
Clinicians can recognize addiction by noting the following behaviors56,57:
History of previous substance abuse by the patient and/or family are strong indicators of the likelihood of continued abuse.56,57 Appropriate medical use of opioids is not generally thought to be associated with addiction.
Pseudoaddiction is commonly seen in patients with severe, unrelieved pain. Patients become preoccupied with finding opioids. Their underlying focus, however, is on finding relief for their pain. Pseudoaddiction may be differentiated from true addiction because drug-seeking behaviors typically resolve when pain is adequately controlled.58,62
Opioids and Drug Abuse
The US Department of Health and Human Services sponsors the Drug Abuse Warning Network (DAWN).63 DAWN reports the frequency of emergency department (ED) drug abuse- related visits and the total drug mentions for nonmedical purposes. Information was gathered from a representative sample of 21 metropolitan EDs (437 hospitals participated in 2002). In 2002, there were approximately 670,000 visits to the ED that were related to drug abuse.57 The visits were categorized, and 7 categories accounted for more than 80% of all drug mentions: alcohol in combination, cocaine, heroin, marijuana, benzodiazepines, antidepressants, and analgesics. About 10% (119,185) of drug mentions involved narcotic analgesics. Trends in opioid abuse have changed over time (Table 11).64 Figure 2 shows the likelihood of drug abuse between short-acting and long-acting opioid analgesics.63
Opioid Use in Clinical Practice
In 1998, the Federation of State Medical Boards created model guidelines for the use of controlled substances for the treatment of pain.65 In May 2004, these were adopted as policy.66 As opioids are the standard of care for chronic pain, clinicians should perform thorough patient evaluations, obtain informed consent for an appropriate opioid treatment plan, periodically assess for opioid efficacy and ADEs, and maintain adequate documentation. Clinicians may follow several practical pointers to differentiate between drug-seeking behavior and medical necessity of opioid use. Maintenance of archived, complete medical records is vital. In addition, an agreement between the clinician and patient may curtail drug-seeking behavior; such a document might include an agreement to seek services only from 1 doctor and 1 pharmacy, reasonable treatment goals, no early refills or changes in therapy without an office visit, no illicit drug use, and as-needed urine drug screens or serum monitoring.17,56 Knowledge of federal and state regulations restricting opioid use is also fundamental. A lawful prescription for a controlled substance must be issued for a legitimate medical purpose by an individual practitioner acting in the usual course of his or her professional practice and must be documented in the medical records. Federal law does not preclude the use of opioids as analgesics for legitimate medical purposes, including treating chronic pain and treating pain in addicts. However, federal law does prohibit the use of opioids to maintain an addicted state without special registration.
Pharmacist's Role in Chronic Pain Management
Pharmacists are key members of the interdisciplinary approach to the management of chronic pain.7 Because of their knowledge of opioid medications, pharmacists can provide valuable information on the most appropriate opioid for pain management and perform a comprehensive review of past and current pharmacologic interventions.7,67 To alleviate concerns about addiction, pharmacists can educate patients about the principles of tolerance, dependence, addiction, and pseudoaddiction. Pharmacists play a vital role in the safe delivery of pain medications by providing pain medication education and "clinical pearls"; maintaining updated and easily accessible equianalgesic conversion tables; assisting in the conversion between changes in medications and routes of opioid therapy; and assisting in the monitoring of opioid therapy for safety and efficacy.67,68
Long-acting opioids are safe and effective when used appropriately for the management of chronic pain and may be rotated to gain better pain control by using equianalgesic tables. Treatment-induced addiction are rare. Documentation and knowledge of regulations regarding opioid use are essential. The best analgesic results are obtained when a therapeutic alliance between the patient and health care professional is formed.
Melinda Jean Throm, PharmD, BCPS: Assistant Professor, Department of Pharmacy Practice, College of Pharmacy - Glendale, Midwestern University; Jeffrey Fudin, BS, PharmD, RPh, DAAPM: Clinical Pharmacy Specialist in Pain Management, Stratton VA Medical Center; Adjunct Associate Professor of Pharmacy Practice, Albany College of Pharmacy; & James A. D. Otis, MD: Director, Pain Management Group, Boston Medical Center; Director of Neurology Residency Training, Boston University
For a list of references, send a stamped, self-addressed envelope to: References Department, Attn. A. Stahl, Pharmacy Times, 241 Forsgate Drive, Jamesburg, NJ 08831; or send an e-mail request to: email@example.com.
CE ANSWER FORM INSTRUCTIONS
TESTING AND GRADING PROCEDURES
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CE REVIEW QUESTIONS
This educational lesson will be available to pharmacists on-line at www.pharmacytimes.com.
(Based on the article starting on page 88) Choose the 1 most correct answer.
1. The International Association for the Study of Pain defines pain as an unpleasant sensory and emotional experience:
2. Unrelieved pain affects the patient's quality of life and also may affect:
3. Barriers to effective pain management include all of the following except:
4. Patients with chronic pain receiving opioids develop tolerance to all of the following opioid-induced adverse drug events except:
5. A cancer patient reports an allergy to morphine (throat swollen shut). The most appropriate alternative opioid in this patient is:
6. Advantages of long-acting opioids include:
7. Which of the following opioids is most appropriate for acute pain management in a 73-year-old woman with seizure disorder and end-stage renal disease on dialysis?
8. Which of the following opioids is most appropriate for chronic pain management in a 55-year-old man with chronic, stable end-stage alcoholic liver disease?
9. Recommended routes of administration for chronic opioid use include all of the following except:
10. A patient is to have all medications crushed and administered through the nasogastric tube. The patient reports an allergy to fentanyl transdermal patches (erythematous rash with blisters). The most appropriate long-acting opioid is:
11. All of the following are unique properties of or considerations regarding methadone except:
12. All of the following are indications for the fentanyl transdermal system except:
13. How do the potencies of morphine and fentanyl compare?
14. Which of the following statements is incorrect regarding physical dependence?
15. Which of the following statements is incorrect regarding addiction?
16. Equianalgesic tables do not take into consideration cross-tolerance. When changing from oral morphine to oral hydromorphone, it is most appropriate to:
17. Drug-related behaviors predictive of addiction include:
18. Which of the following should be used in the management of patients when they are receiving a narcotic for chronic pain?
19. Because of federal and state laws governing the prescribing and dispensing of Schedule II narcotics, clinicians should:
20. Which of the following roles may a pharmacist play in chronic pain management?