U.S. Pharmacist

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Acute Pain Pharmacotherapy

Scott A. Strassels, PharmD, PhD, BCPS
Assistant Professor, Division of Pharmacy Practice, University of Texas, Austin, Texas

Ewan McNicol, PharmD, MS-PREP
Tufts–New England Medical Center,
Boston, Massachusetts

Rosy Suleman, PharmD
Regional Scientific Associate Director
Novartis Pharmaceuticals Corporation
Carlsbad, California

5/18/2007

US Pharm. 2007;32(5):HS-5-HS-19.

Millions
of people in the United States undergo surgery or are injured each year.1 Yet, for people from all different backgrounds and in various stages of life, as well as those with underlying medical conditions, the treatment of pain is less than ideal.2-10 This issue reflects deeply seated issues pertaining to all levels of the health care system and society. Furthermore, undertreated pain has important clinical, economic, and human outcomes. Effects include increased catabolic demand, decreased movement, cough suppression, and shallow breathing; increased use of medical resources; and reduced health-related quality of life (including diminished physical functioning).11-17 Evidence indicates that cellular and molecular changes seen in chronic pain begin to appear with the initial injury, supporting the observation that undertreated acute pain is a risk factor for chronic pain and that acute and chronic pain exist on a continuum.18

The systematic undertreatment of pain represents a public health crisis in this country. While all health care professionals must have knowledge of the tools used to help treat pain, pharmacists have a particularly significant role because they are highly visible and accessible members of the health care team. The purpose of this article is to review clinical issues related to the pharmacotherapy of acute pain that community-based pharmacists are likely to encounter. Before the pharmacotherapy of acute pain is discussed, it is important to ensure the use of a common language to help avoid the impassioned and often mistaken use of vocabulary that contributes to existing pain management obstacles.

Defining Pain
According to the International Association for the Study of Pain (IASP), pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage.19 Pain may be described in terms of this damage. The definition of pain is often subjective, being whatever the person says it is, existing whenever the person says it does.20

From these definitions, it is clear that pain is a complex, multidimensional, subjective experience, and that the relationship between tissue damage and pain intensity is variable. Additionally, the inability to communicate the presence of pain does not in any way suggest that pain is absent. Because pain is subjective, health care providers must rely on the person's report, even when reported pain and behavior do not seem to match.

While pain is often described using terms like acute and chronic, these and other distinctions can be misleading. For example, acute pain is often described as a recent onset that tends to diminish with time, while chronic pain tends to last longer than is expected for the injury to heal.21 Acute pain can be long-lasting; people often do not conform to expectations; and mixed types of pain can be present at the same time. For example, patients with cancer may experience pain that is acute, chronic, or some hybrid of these concepts. Other examples include a person with chronic arthritis pain who undergoes surgery, a person with cancer-related pain who also experiences episodes of breakthrough pain, or a person with low back pain who is injured in a car accident. In each setting, the affected patient will experience pain with mixed features.

Pain is commonly referred to in terms that reflect the underlying location or pathophysiology, such as nociceptive or neuropathic.19,20 Nociceptive pain results from pressure, temperature, or chemical stimuli. This type of pain is also classified as originating from skin, bones, muscle, and connective tissue (somatic) or internal organs (visceral).20 In general, somatic pain tends to be specifically located, while visceral pain is more diffuse. In contrast to nociceptive origins, nerve or nervous system damage may result in neuropathic pain.19 This type of pain may be central, as with some poststroke syndromes, or peripheral, such as diabetic neuropathy or postherpetic neuralgia.

Dependence, Tolerance, and Addiction
Much of the confusion about pain management involves these concepts. Yet, rather than allowing this confusion to interfere with the ability and willingness of clinicians to provide effective pain management, pharmacists and their colleagues on the health care team, patients, and families must be educated about these phenomena.

If a patient taking a drug develops a withdrawal syndrome when that substance is suddenly removed, the individual is physically dependent on that substance.22 For opioid analgesics, the withdrawal syndrome generally includes signs of central arousal, such as insomnia, irritability, and agitation. Patients may also experience autonomic symptoms, including diarrhea, rhinorrhea, and sweating, as well as muscle spasms, gastrointestinal cramping, and other painful phenomena.

It is critically important to understand that dependence is an expected physiologic response to use of certain drugs and neither a sufficient nor a necessary aspect of addiction. 22-24 Although we often think of dependence relative to use of opioid analgesics, this concept also applies to any other drug (or pharmacologic class) for which suddenly stopping use is discouraged. Typically, the best way to avoid development of a withdrawal syndrome in a person thought to be dependent on a drug is to slowly decrease the dose.

Similarly, tolerance refers to the need for increased doses to produce a particular effect.22 For a given drug, however, a person may become tolerant to some effects but not to others. For example, with the opioid analgesics, tolerance to sedation and respiratory effects typically develops quickly, while people generally develop tolerance to the constipating effects of these drugs slowly, if at all. For this reason, a preventive bowel regimen is considered a routine part of therapy for individuals expected to be on opioid analgesics for an extended period of time.

Addiction is probably one of the most misunderstood phenomena associated with the use of opioid analgesics. As defined by the American Pain Society, American Society of Addiction Medicine, and American Academy of Pain Medicine, this primary, chronic, neurobiological disease has genetic, psychosocial, and environmental dimensions.22-24 Addicted individuals may have impaired control over their drug use, compulsive use of the substance, continued use despite harm, and craving for the substance. Furthermore, evidence in biomedical literature overwhelmingly indicates that the rate of iatrogenic addiction among persons who are being treated for acute pain, and who do not have a history of substance abuse, is vanishingly low.25-29 This evidence and our understanding of addiction support the contention that people who use opioid analgesics to relieve their pain on a mutually agreed-upon schedule without aberrant behaviors, whose functioning and pain control are relatively stable, and who are willing to consider various treatment options are unlikely to become addicted.22-24 As a result, concern about causing a patient to become addicted should not contribute to clinical decisions about how to treat pain, nor to patients' willingness to use appropriately prescribed analgesics.23,25-29

While evidence indicates that the risk of iatrogenic addiction in persons who are treated for acute pain is nearly zero, systematic undertreatment of pain--including use of subpotent analgesics, dosing regimens that do not reflect the pharmacokinetics and pharmacodynamics of the analgesic, and inappropriate reliance on as-needed use of these drugs--is common. Moreover, not only does the systematic undertreatment of pain unfairly penalize persons with pain, it can also directly result in a phenomenon known as pseudoaddiction.30 In this syndrome, the patient may (unsurprisingly) request analgesics before the next scheduled dose, doctor-shop, and act in other ways that are seen in persons who abuse substances. The distinction is that when an undertreated individual's pain is appropriately treated, these aberrant behaviors disappear. Rather than waiting for a problem to develop, however, pseudoaddiction can be avoided by building trust between the patient and the health care team, using analgesics on a regular schedule instead of an as-needed basis, and using adjuvants and nondrug treatments.

Evidence of Undertreated Pain
During the past four decades, there have been numerous published reports of suboptimally treated pain among persons with acute pain.2-10 Progress in improving the care for these individuals has continued, but it has been done slowly and fitfully and has been less successful than might be expected, given the availability of potent analgesics and clinical practice guidelines to help clinicians.3,31-33 Well-documented barriers to effective evidence-based pain management include deficiencies in pre- and postgraduate health professions education; incorrectly held attitudes and beliefs about opioid analgesics, adverse effects, and pain itself; and fear of prosecution. 3,34-41

Pain Pharmacotherapy
Nonopioids: These drugs include salicylates, acetamino­phen, and the NSAIDs. They are at least generally familiar to almost everyone, since they are nearly ubiquitous in prescription and OTC medications. These drugs are used primarily for mild to moderate pain, although in combination with opioids, they are often used for more intense pain.

Acetaminophen is a centrally acting analgesic that does not have significant anti-inflammatory activity, nor does it affect platelets or gastric mucosa.42 Despite a generally favorable toxicity profile, acetaminophen must be used cautiously because it is potentially hepatotoxic, particularly in persons with hepatic or renal disease, chronic alcoholism, or malnutrition. Even in otherwise healthy adults, the maximum daily dose of acetaminophen from all sources should not exceed 4,000 mg.42,43 This is important because acetaminophen is used in fixed-combination drugs with opioid analgesics. While there is no set ceiling dose for opioids, there is a clearly identified limit for acetaminophen, which can result in an unnecessary, artificial barrier to optimal analgesia.

Additionally, the rectal absorption of acetaminophen is variable, and this can affect the doses needed to provide pain relief. For example, although the recommended pediatric oral dose of acetaminophen is 10 to 15 mg/kg every six hours, a rectal loading dose of 40 mg/kg with maintenance doses of 20 mg/kg every six hours has been found to be safe and effective in at least one study.44,45

NSAIDs are also commonly used for a wide variety of painful conditions and have proven effective in treating postoperative pain. As their name suggests, these agents inhibit central and peripheral prostaglandin synthesis, diminishing inflammation. Yet, because NSAIDs do not affect circulating pros­ taglandins, pain relief occurs sooner than anti-inflammatory effects.18 As with acetaminophen, the NSAIDs have a ceiling effect, beyond which therapeutic benefit does not increase, but the risk of adverse effects, including nausea, vomiting, and gastrointestinal bleeding, does increase. This observation is particularly important, since NSAID use results in significant morbidity and mortality in the U.S. Despite these well-described risks, the risk-benefit ratio of NSAIDs remains generally favorable in terms of their therapeutic potential.

Cyclooxygenase-2 (COX-2) Inhibitors: Many questions remain about the possible role of COX-2 selective inhibitors in clinical practice. While these drugs are similarly efficacious to nonselective NSAIDS, the main argument for use of COX-2 inhibitors has always been safety, and it is here that many unresolved issues persist. For example, rofecoxib and valdecoxib were withdrawn from the U.S. market for safety concerns. In addition, in a large, randomized trial, individuals with rheumatoid arthritis or osteoarthritis who took celecoxib had fewer symptomatic upper GI ulcers and related complications than individuals who took ibuprofen or diclofenac over the first six months of use, although this benefit disappeared by the end of one year of use.46,47 There is also some evidence suggesting that a clinically important drug interaction may occur between warfarin and COX-2 inhibitors.48,49 Other compounds in this class are in various stages of clinical development; thus, it remains to be seen whether the benefit in persons with arthritis occurs immediately and if this effect is broadly generalizable.

Opioids: Without a doubt, opioids have an important and useful role in the treatment of moderate to severe pain. Notably, these drugs should not be referred to as narcotics, a term that has been associated with barriers to optimal pain management and that fails to clearly identify the specific type of drug.23

Opioids are often classified by their activity at mu, kappa, or delta receptors in the central nervous system.50,51 Effects of the mu- and kappa-receptor agonists include analgesia. Mu-agonists also affect mood and reward behavior, and while kappa-active drugs may produce less respiratory depression and miosis, these drugs are also associated with dysphoria. It is important to remember that in the dosage range typically used to treat acute pain, the mu-receptor agonists have no therapeutic dosage ceiling.50,51 Provided that the person is getting pain relief and is not having intolerable side effects, the dose of the opioid analgesic can be increased. Opioid analgesics also lack the adverse effects associated with NSAIDs, and people who do not respond to one opioid may still respond to another.

Currently available opioid analgesics and antagonists are listed in Table 1. Most of the opioid analgesics are mu-receptor agonists, although several are mu-receptor antagonists and kappa-receptor agonists. The mixed-activity drugs (once commonly called mixed agonist-antagonists) were designed to provide a lower risk of respiratory depression and abuse but when used in equianalgesic doses, their rate of adverse effects is comparable to that of the mu-receptor agonists.50,51 Furthermore, there is a consistent dose-response relationship with the mu-receptor agonists, but the kappa-receptor agonist/mu-receptor antagonist drugs are not thought to possess that quality.




Opioids to Avoid: The role for codeine, meperidine, and propoxyphene in acute pain management is limited, regardless of the route of administration. Codeine is a prodrug and must be converted to morphine via the cytochrome P-4502D6 pathway.53 About 10% of a codeine dose is converted to morphine, which is about 30% bioavailable. As a result, 30 mg of codeine provides just 1 mg of morphine. Persons who lack the ability to metabolize codeine to morphine get no analgesia from the drug, although they are still at risk for dose-limiting adverse effects, which commonly occur.51

Meperidine is about 1/10 as potent as morphine on a milligram-to-milligram basis; thus, a 75-mg dose of meperidine is equivalent to about 5 to 7.5 mg of morphine.3 A dosing interval of four to six hours is often used for meperidine, but the drug provides analgesia for 2.5 to three hours. As a result, 100 to 150 mg of meperidine every three hours would be needed to provide analgesia equivalent to 10 mg of morphine every four hours.3

 

Meperidine's active metabolite normeperidine is renally eliminated. Normeperidine is neurotoxic and can cause a variety of serious adverse effects, including seizures, even in persons with normal renal function.23,53,54 Additionally, concomitant therapy with meperidine and monoamine oxidase inhibitors (MAOI) (or use within two weeks of discontinuation of the MAOI), including seligilene, is absolutely contraindicated due to a risk of hypertensive crisis, hyperpyrexia, and cardiovascular system collapse.55 Use of meperidine should be avoided whenever possible. If use of this analgesic is unavoidable, American Pain Society guidelines recommend use for no more than 48 hours and at doses no more than 600 mg per 24 hours in persons with normal renal function.3

Propoxyphene has no clinical advantages over acetaminophen.3,56 Like meperidine, propoxyphene also has an active, toxic metabolite norpropoxyphene that accumulates in persons with decreased renal function.53,57 This metabolite is also associated with an increased incidence of falls in elderly individuals.58

Equianalgesic Conversion: Morphine is the prototypical opioid analgesic. However, there are times when it is desirable to use one of the other drugs in this class. For example, an individual may be allergic or hypersensitive, intolerable adverse effects may occur, or the drug may not provide the desired degree of pain relief. Pharmacokinetic considerations may also have an impact. For example, neither hydromorphone nor oxycodone have clinically active metabolites, so these agents are often preferred in people with diminished renal function.

At equianalgesic doses, the opioid analgesics have similar efficacy, although adverse-effect profiles may vary. There are a variety of dose-conversion tables and methods available, and different results are common depending on the method used. Some evidence also suggests that conversion factors differ based on the drug used, the drug that it is being converted to, and whether the person is opioid-naïve or opioid-tolerant.21,59,60

A good example of this phenomenon is methadone. While methadone was once used mainly for opioid maintenance programs, its use as an analgesic has increased substantially over the past few years. As a result, pharmacists in community practice are much more likely to encounter its use. Methadone is generally considered to be equipotent to morphine in opioid-naïve individuals, but its elimination half-life is much longer than its biologic half-life, and it is also an N -methyl-d-aspartate (NMDA) receptor antagonist. As a result, large decreases in methadone doses (~90%) may be needed over the first few days after changing analgesics. Failing to account for this phenomenon can contribute to serious and even fatal adverse events.

Several methods for calculating equianalgesic doses are used; some use tables in pharmacy references commonly available, while others take relative potency and pharmacokinetic parameters into account.21,59,60 Two of these methods are shown in Table 2; however, it is important to recognize that major differences between methods can result. For example, converting from morphine to oxycodone using method 1 in the table indicates that 48 mg of intravenous morphine is equivalent to 96 mg of oral oxycodone, while using method 2 provides a result of 60 mg of oral oxycodone. One difference between these approaches is that in the first method, 20 mg of oral oxycodone is considered to be equivalent to 30 mg of oral morphine. This conversion factor is frequently used, but for this to be true, oxycodone would have to be about 50% bioavailable, rather than 80%.21 Method 2, in contrast, accounts for potency and bioavailability of these drugs.




To help avoid cases of serious overdose, one approach is to decrease the dose of the new opioid by approximately 25% to 50% to account for incomplete cross-tolerance. However, the percentage decrease depends on how well the person's pain is being controlled, among other factors.61

Role of Community Pharmacists
There is ample evidence documenting pharmacists' impact in helping reduce adverse drug events and their associated costs in hospitalized persons.61-63 Thus, it is logical to question how to best assess the contribution that community-based pharmacists can make to patient outcomes. An example of this effort was described in a study on the feasibility of health outcomes assessment in community pharmacy practices.64 Individuals who participated in this project had been diagnosed with osteoarthritis, rheumatoid arthritis, or low back pain, among other musculoskeletal disorders. Study participants met with a pharmacist every three months for a year and completed a survey that included condition-specific items and the SF-36, as well as questions about the use of medical resources. The SF-36 is used to estimate the effects of illness or medical conditions on health-related dimensions of quality of life that are believed to be universally important and are not age, treatment, or disease specific.65 Data collected in this study help indicate how these conditions affect health-related quality of life. There is no way to understand the effects of health care on individuals unless health care providers ask. This information can help identify people who experience adverse effects from their medications or who need additional attention in order to improve their therapeutic regimen. Possibly more important, these data show that it is possible to collect this information in community pharmacies. Given the numerous demands on pharmacists' time and attention, it is encouraging to see the potential of community pharmacists to contribute to patient care.

There are a wide variety of ways that pharmacists can help care for persons with pain. Their roles include compounding and dispensing; serving as a resource for clinicians, patients, and family members; advocating on behalf of patients suffering from pain; and helping ensure continuity of care.66 As the number of people who undergo outpatient surgical procedures rises and pressure increases to discharge hospitalized individuals as soon as they are medically stable, this latter point will become increasingly important.

Conclusion
The promise of relief from pain exerts a powerful attraction, leading people in distress to seek medical care. Pain is a universal part of being human, and yet, evidence demonstrates that people from all backgrounds, stages of life, and levels of health experience less than optimal treatment of their pain. This situation exists for many reasons that pertain to our health care system and society.

Improving pain management is complex and multidimensional--much like pain itself--and there are many important challenges clinicians must face. Yet, there is good news: Because of pharmacists' visibility and ready accessibility, there are ample opportunities for us to become leaders in this effort.

 

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