Analgesic Selection

Analgesic Selection

The selection of an analgesic must be individualized for each patient, depending on the cause and chronicity of the pain as well as the patient's age and concomitant medical conditions that may alter drug response. Furthermore, the clinical response of the patient dictates future dose adjustment, route, and desired dosing interval. The selection of an opioid for the management of severe acute and chronic malignant pain must always include consideration of morphine or one of the other potent opioids; however, the role of NSAID should not be overlooked. Adjunctive analgesic medications, such as antidepressants or anticonvulsants, are often added because chronic nonmalignant pain can be associated with sympathetic dysfunction and neuropathies. An NSAID is the analgesic of choice in the management of mild to moderate pain involving musculoskeletal tissues and also are extremely effective in the management of pain from bony neoplastic metastasis. Neurogenic pain often responds better to tricyclic antidepressants (TCA) than to opioids. Neuropathic pain may not be relieved by opioids until the dose is high enough to also cause significant side effects.

 

If the maintenance dose of an opioid analgesic is too high, the patient can become oversedated and less functional. In extreme cases, patients may become bedridden from excessive opiate use. When given the choice of eliminating the last trace of discomfort at the cost of some sensorial clouding, patients invariably select full alertness and the continued presence of some pain.^38,39 Patients who are receiving opioids also need to be monitored for deterioration in vital signs (pulse and respiratory rate), constipation, and urinary retention. Stool softeners and other prophylactic measures, such as stimulant laxatives, may be required. Similarly, a patient who is receiving NSAID or adjunctive analgesics should be monitored for possible untoward side effects associated with such medications.

 

Orally or transdermally administered analgesics allow a patient a greater degree of independence and control over daily activities than parenteral administration by maximizing mobility. Similar advantages can be obtained with an intravenous (IV) infusion device, particularly a portable programmable infusion pump. Regular parenteral administration by other routes can be difficult and painful in cachectic patients.

Low to Moderate Potency (Mild) Analgesics

 

The nonsteroidal anti-inflammatory analgesics have a relatively flat dose-response effect when contrasted with opioids, reaching maximal analgesia at low to moderate doses. In contrast to opiate analgesics, higher doses of NSAIDs do not produce greater analgesia. These drugs are frequently prescribed at doses in excess of the effective maximal analgesic dose, however, because the duration of analgesia can increase with higher doses. For example, ibuprofen given 600 mg every 6 hours produces a similar analgesic effect as 400 mg given every 4 hours. The total daily dose is the same, but side effects are experienced more often with larger doses. Although NSAIDs have both analgesic and anti-inflammatory properties, it is often difficult to differentiate between these effects in published studies or during clinical use in patients, as the time courses of each effect overlap.

 

All of the NSAIDs, including ibuprofen (Motrin), naproxen (Naprosyn), naproxen sodium (Anaprox), diflunisal (Dolobid), diclofenac (Voltaren), diclofenac potassium (Cataflam), nabumetone (Relafen), ketoprofen (Orudis), flurbiprofen (Ansaid), ketorolac (Toradol), and others, provide analgesia equivalent or superior to that of aspirin^40,41 or acetaminophen codeine 60 mg combined with a variety of mild to moderate painful conditions.^42,43 As with the opioid analgesics, the duration of action of an NSAID does not correlate well with the serum half-life of the drug. Likely, this is because the analgesic effect arises from central mechanisms, and is related to the exposure of the CNS to adequate drug levels. Patient response should guide the clinician in selecting dosing intervals of these agents, especially when they are combined with opioids.

 

Opioid Analgesics

In general, opioids are more effective for treating severe pain than nonopioid analgesics such as NSAIDs, although the range of potencies is wide with this class of medicines. They are generally recommended for moderate to severe pain intensity and are used in chronic pain syndromes that are refractory to other classes of agents.

 

An intramuscular (IM) dose of 10 mg/70 kg of morphine sulfate provides significant analgesia in approximately 70% of patients with severe pain. The remaining 30% of patients require higher doses,⁴⁴ which not only increase the intensity and duration of analgesia, but also the incidence of side effects. Morphine dosage requirements also vary with the severity of pain, individual perceptions of pain, age, opioid tolerance or previous exposure, and the presence of concomitant diseases. Thus, single parenteral analgesic doses of morphine ranging from 4 to >20 mg are used to treat acute pain and parenteral doses as high as 200 mg/hour have been required to treat end-stage malignant pain in patients who have developed tolerance.

A 10-mg parenteral dose of morphine is the historical reference standard by which all other opioid analgesics are compared. Therefore, morphine equivalents are often used when calculating analgesic doses for other opioids. The duration of analgesia of an opioid correlates partially with its serum half-life, but also with the dose, route of administration, and the distribution characteristics of the drug.⁴⁵ For example, methadone has a very long serum half-life of 24 hours, but its duration of analgesia is only about 6 hours. On the other hand, single daily doses of methadone are retained on opiate receptors in the brain long enough to prevent abstinence symptoms for 24 hours in opiate abusers. When used for pain management, the long half-life of methadone may contribute to cumulative effects and drug toxicity such as QTc prolongation. When methadone is administered epidurally, its duration of analgesia is short because of its high lipophilicity that promotes rapid redistribution from the epidural space into systemic circulation, and consequently, metabolic clearance. Conversely, morphine has a relatively short duration of analgesia when administered parenterally, but when it is administered epidurally, it has a long duration of analgesia because of its low lipophilicity, which inhibits its redistribution from the epidural space.

The administration of opioid analgesics is frequently complicated by the need to convert between different routes of administration or different opioid formulations. The approximate equianalgesic doses of parenteral and oral opioid analgesics are listed in Table 8-3. The specific oral-to-parenteral ratios of these drugs also are listed in Table 8-3; however, the precision of these ratios is controversial, in part because of the methodologies used to infer these “equivalencies.” For example, most investigators maintain that the oral-to-parenteral ratio for morphine is 6:1, but some hospice clinicians maintain that morphine's oral-to-parenteral ratio is closer to 2:1. Such confusion may result from differences in the design of single-dose versus multiple-dose clinical trials. First-pass hepatic metabolism may be greater in single-dose clinical studies than in multiple-dose studies because first-pass metabolic pathways can become saturated with repeated doses. Furthermore, the accumulation of the active metabolite morphine-6-glucuronide after chronic dosing may contribute to the clinically observed differences. When all factors are taken into account, the bioavailability of oral morphine varies from 17% to 70% of a dose; therefore, it is reasonable to expect individual patient response to be highly variable.^46,47 No matter which ratio the clinician uses, the dosing must be guided by the patient's clinical response and frequent clinical reassessment.

If an opioid analgesic is to be substituted with another opioid, the equivalent doses as listed in Table 8-3 can be used as an approximate guide to dosage conversions unless the patient has developed tolerance. Cross-tolerance between opioid analgesics exists, but is often not complete. Therefore, calculated doses may be reduced by as much as 50% when interchanging different opioids. This is especially true when switching to methadone from other opioids.⁴⁸ Patient comfort is the goal, and the response of the patient should always be the basis for dosage adjustments. Whenever a new opioid analgesic is initiated, the patient's response should be assessed within the first few hours because the initial dose of the new analgesic is only correctly estimated about half the time. Frequent reassessment of clinical responses should facilitate dosage adjustments and control the patient's pain more quickly.

The analgesic efficacy of propoxyphene and combinations of acetaminophen with propoxyphene 65 mg remains controversial. Most double-blind studies demonstrate no advantage of propoxyphene alone over aspirin, acetaminophen, or codeine in relieving various types of pain.^49,50 This lack of benefit conflicts with the observation that propoxyphene in combination with acetaminophen remains a commonly prescribed regimen in the United States. This may be partially explained by an additive or synergistic effect when opioids are combined with nonopioid analgesics. Another possible explanation is the tendency of many patients to take more than the prescribed doses. Because propoxyphene has a 13-hour half-life, repeated doses taken every 4 to 6 hours for several days can result in significant drug accumulation. Furthermore, analgesic assessments of propoxyphene efficacy have been based primarily on single-dose studies,⁵¹ while most patients take as many as 10 to 12 tablets daily. Propoxyphene has significant CNS effects. At lower dosages, propoxyphene can produce mild CNS depressant effects. At higher dosages, however, it can have an amphetaminelike stimulant effect and, in overdoses, propoxyphene can produce seizures. As with other opioid analgesics, propoxyphene can produce physical dependence.

 

As with all opioid analgesics, patients taking propoxyphene need to be warned about the risks of concurrent alcohol use, the operation of equipment or machinery requiring mental acuity, and the potential for agitation and sleeplessness when the medication is discontinued abruptly after prolonged use. In addition to effects on the CNS, propoxyphene has been associated with hypoglycemia in patients with renal dysfunction.⁵²

Table 8-3 Properties of Opioid Analgesics

Parenteral Dose (mg) Oral Equivalent Routes Onset (min) Duration (hr) t1/2 (hr) Notes Opioid Agonists for Moderate to Severe Pain (mu Receptor Agonists) Phenanthrenes Morphine (various) 10 30 PO, parenteral, PR IV: 5 PO: 60 3–6 2–3 Sustained release PO preparations available Hydromorphone (Dilaudid) 1.5 7.5 PO, parenteral, PR See morphine 3–6 2–4   Levorphanol (Levo-Dromoran) 2 4 PO, SC, IM 30–90 4–6 4–16 Accumulates with chronic dosing Oxymorphone (Numorphan) 1.5 N/A Parenteral, PR 10–90 3–6 3–4   Phenylpiperidines Fentanyl (Sublimaze) 0.1 N/A IV, spinal, buccal, patch 10 1–2 3–4 Nonlinear kinetics with repeat dosing Sufentanil (Sufenta) 10 mcg N/A Parenteral, spinal 10 2–4   Duration may be dose-related Diphenylheptanes: Methadone (Dolophine) 10 5 PO, SC, IM 60 6–8 21–25 Accumulates with chronic dosing Opiods for Mild to Moderate Pain (mu Agonists) Phenanthrenes Codeine (various) 120 200 PO, parenteral, PR See morphine 3–6     Hydrocodone (various) N/A 30 PO   30–60 3–4   Oxycodone (various) N/A 20 PO   30–60 4–6   Dihydrocodeine (various) N/A 30 PO   30–60 4–6   Phenylpiperidines Meperidine (Demerol) 100 400 PO, parenteral 15–60 1–3 3–4 Normeperidine is a CNS irritant Partial Agonists/Antagonists (mu and/or Kappa Agonists With or Without mu Antagonism) Buprenorphine (Buprenex) 0.3 N/A SC, IV, IM 1–5 4–6 2–3 Not naloxone reversible Butorphanol (Stadol) 2 N/A SC, IV, IM, intranasal 15–45 3–4   Dysphoric Nalbuphine (Nubain) 10 N/A SC, IV, IM 1–5 4–6 2–3 Respiratory ceiling Opioid Antagonists Naloxone (Narcan) 0.40.8 N/A IV 10 2–3 1–1.5   Naltrexone (Trexan) N/A 50 PO 30–60 24–72 9–17 Duration dose-dependent NOTE: Most analgesic equivalents were derived from single dose studies. CNS, central nervous system; IM, intramuscular; IV, intravenous; N/A, not applicable; PO, orally; PR, by rectum; SC, subcutaneously. Adapted from Principles of Analgesic Use in the Treatment of Acute Pain and Cancer Pain. 5th ed. Glenview, IL: American Pain Society; 2003:1417, with permission.

Differentiating Between Clinical Opioid Use and Drug Abuse

When using opiates to treat severe pain lasting more than a few days, several phenomena can occur. The terms used to describe these phenomena are tolerance, physical dependence, and pseudoaddiction. Clinicians must understand the differences and the context in which these phenomena occur to differentiate between expected developments and drug abuse. Much of the fear and reluctance to use opioid analgesics result from misunderstandings of these natural events by clinicians, patients, and caregivers.

Tolerance to the analgesic effects of opiates is a common physiologic finding that results from neuroadaptation by the body during chronic use.⁵³ It may be seen after several days of therapy and can be first recognized by a decrease in the duration of analgesia. Patients who develop tolerance require an increase in the opiate dose to achieve the same level of analgesia. Tolerance to opiates occurs fairly slowly, but should be anticipated in all patients requiring continuous opiate therapy, such as critical care patients or patients with chronic painful conditions. These types of patients should be informed that the need for increasing doses is an expected occurrence and does not indicate addiction.

Physical dependence is a natural physiologic process that occurs with chronic opioid administration.⁵³ Signs and symptoms of physical dependence are summarized in Table 8-4 and are seen only when opiates are stopped abruptly or the dose is markedly decreased. Physical dependence does not indicate addiction, and the difference should be made clear to patients and their caregivers. The symptoms of physical dependence may be observed in critical care patients who have their doses of opioid analgesics tapered too rapidly or in patients requiring chronic opioid therapy who are unable to obtain an adequate supply of medication or who are undertreated. Unintentional physical withdrawal can also occur if metabolic enzyme inducers, such as phenytoin, are added to a chronic pain regimen. Early symptoms of abstinence can include irritability and restlessness, and onset occurs within 6 to 24 hours of the time the last opioid dose was administered. Later, a person develops chills, sweating, joint and muscle pains, and gastrointestinal (GI) distress, including emesis and diarrhea with abdominal cramping. The time of onset is correlated to the drug's half-life, to the average doses required by an individual, and to the pattern and history of opioid dosing. For example, abstinence induced by tolerance to hydrocodone (a drug with a short half-life) can be anticipated to develop in 4 to 6 hours after the last dose, whereas with methadone it may not occur for 24 to 48 hours after the last dose. Similarly, the abstinence syndrome can last longer when associated with long-acting agents. For short-acting agents (e.g., hydrocodone or oxycodone), abstinence may resolve within 48 to 72 hours, whereas for drugs such as methadone, it may last as long as several days. Mood swings, myalgia, and arthralgia can persist for as long as several weeks after the last dose of an opioid.

Table 8-4 Signs and Symptoms of Opiate Physical Dependence

Rhinorrhea (runny nose) Lacrimation (tearing) Hyperthermia, chills Muscle aches (myalgia) Emesis, diarrhea, gastrointestinal cramping Anxiety, agitation, hostility Sleeplessness Symptoms begin within 6 hours for short-acting opioids (e.g., morphine) and generally peak in approximately 36–48 hours. Symptoms of abstinence usually subside within 3 to 7 days (average, 5 days). With methadone, however, abstinence syndrome develops more slowly, and is less severe, but protracted. Opioid antagonists or mixed agonist–antagonist drugs can precipitate abstinence in some patients after chronic or subchronic opioid exposure.

Addiction to opioid analgesics is characterized by a dysfunctional pattern of use for purposes other than alleviation of pain. It may involve adverse consequences of opioid use, loss of control over their use, and preoccupation with obtaining opioids despite the presence of adequate analgesia. It is important to realize that tolerance and physical dependence may or may not be present in addiction and that the presence of tolerance and physical dependency does not imply addiction. Pseudoaddiction is an important type of behavior that clinicians must understand and recognize because it can easily be misinterpreted as addiction.⁵³ Pseudoaddictive behaviors may be seen in patients with severe, unrelieved pain. These behaviors can mimic those seen with addiction. Patients become preoccupied with obtaining opioids; however, their underlying focus is on finding relief for their pain. Their fear of not having an adequate amount of medication available to control their pain may result in medication hoarding. When patients with pseudoaddiction are provided adequate analgesia, the behaviors that mimic addiction resolve, the medications are used as prescribed, and the patient's daily functioning increases.⁵³

 

If opioid misuse is suspected, pharmacists can help both patients and prescribers develop appropriate care plans by being vigilant for warning signs that the patient is not adhering to a care plan. These include prescriptions from multiple physicians or phone calls from unknown prescribers; rapid or unsanctioned escalation of dosing requirements, particularly for nonmalignant pain syndromes; frequent excuses for running out of medication early or requests for “vacation” supplies; lack of requests for adjunct analgesic refills (e.g., antidepressants, anticonvulsants); extreme polypharmacy with multiple CNS depressants or multiple habituating substances; and injecting oral medicines or chewing matrix formulations. Persons demonstrating these traits may require referral to an appropriate substance abuse program.⁵⁴

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