- Email: [email protected]
Pharmacologic Management of Pain
THE SURGEON AND PALLIATIVE CARE
1055-3207/01 $15.00
+ .OO
PHARMACOLOGIC MANAGEMENT OF PAIN The Surgeon's Responsibility James B. Ray, PharmD
Divinum est sedare dolorem-Blessed
are those w h o treat pain. GALEN
Historically surgeons have had to witness their patients' pain probably longer than any specialty within medicine. Until the mid 1800s, in attempts to provide lasting relief from disease, surgeons were required to operate on their fellow man without the aid of anesthesia. In 1846, the same year the first surgical procedure with ether was performed, the American Medical Association's (AMA)First Code of Medical Ethics stated, "A physician ought not to abandon a patient because the case is deemed incurable; for his attendance may continue to be highly useful to the patient, comforting to the relatives around him, even in the last period of a fatal malady, by alleviating pain and other symptoms, and by soothing mental anguish.'12 More recently the AMA stated, "Physicians have an obligation to relieve pain and suffering and to promote the dignity and autonomy of dying patients in their care."14 Embodied within the American College of Surgeons statement on principles guiding care at the end of life is the principle to "ensure alleviation of pain and management of other physical symptoms."' Pain relief in palliative care forms the cornerstone of a comprehensive pattern of care that encompasses the physical, psychologic, social, and spiritual aspects of suffering. From the Department of Pharmacy and Drug Information Services, Hamot Medical Center, Erie, Pennsylvania
SURGICAL ONCOLOGY CLINICS OF NORTH AMERICA VOLUME 10. NUMBER 1 .JANUARY 2001
71
Pain is a common feature in cancer. Thirty to forty percent of patients have pain at the time of diagnosis, and 65% to 85% have pain in the advanced stages of their i l l n e s ~ . ~Pain ~,~ also ~ , commonly ~~ occurs in other progressive malignant (noncancer) diseases such as AIDS, multiple scle~ ~ , from the SUPPORT and rosis, and amyotrophic lateral s c l e r ~ s i s .44~ ,Data HELP studies indicate that pain is often severe in seriously ill and elderly patients and patients with conditions that are not often thought to be associated with pain, such as chronic obstructive pulmonary disease, congestive heart failure, and cirrhosis.17 Pain continues to be universally under-treated in every area of healthcare.4,5,13,60,66 In a society that lives by mottoes such as "no pain, no gain" and "just say no to drugs," pervasive subconscious barriers to effective pain relief exist. In being responsible for effective pain management to the patient, the surgeon must first set aside his or her own beliefs and attitudes regarding pain and its control and be open to change. PAIN PATHOPHYSIOLOGY
Pain can be acute or chronic. Acute pain has a beginning and an end, and is linked to iatrogenic or accidental tissue damage. This type of pain diminishes and resolves within days to weeks of tissue healing. Chronic pain cannot always be clearly related to any known tissue damage. The patient often has no clear recollection of when it began and at times, death may seem the only solution to end his or her pain. Acute and chronic pain may be of a nociceptive or neuropathic origin. The perception of nociceptive pain is caused by direct stimulation of intact mechanical, chemical, or thermal nociceptors and transmission of impulses along normal functioning nerves. Nociceptive pain can be subdivided into somatic and visceral. Somatic pain describes the stimulation of the nervous system within the skin, soft tissue, muscle, and bone. Common descriptors of somatic pain include "sharp," "aching," and "throbbing," and the pain is often well localized. Visceral pain results from stimulation of the autonomic nervous system associated with the heart, lungs, and gastrointestinal and genitourinary tracts. This pain may be more difficult to describe and localize. Both types of nociceptive pain usually respond to opioids and anti-inflammatoryagents. Neuropathic pain is believed to be caused by dysfunction of the peripheral or central nervous system. Common syndromes of neuropathic pain include phantom pain, postherpetic neuralgia, and malignant plexopathies. Patients often describe this type of pain with words like "burning," "tingling," "numbness," "shooting," "stabbing," or "electric-like feelings." Neuropathic pain may respond to opioids, but often a combination of opioids with adjuvant analgesics (tricyclic antidepressants, anticonvulsants, antiarrhythmics) is needed to achieve effective pain control. To be personally accountable for a patient's pain the surgeon must first understand the extent of the problem. Control of postoperative complications like fever or wound dehiscence has paramount importance in
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the surgeon's mind regarding successful outcomes. Because of the impact on physical and psychologic function, poor pain control should be viewed in the same light. Adopting pain as the "fifth vital sign" creates a situation where pain now becomes visible. Assessment and documentation of the intensity of pain along with the other vital signs demands our attention. Using a simple tool to rate the intensity of pain, such as a verbal scale where 0 = no pain and 10 = pain as bad as imaginable, is analogous to using a thermometer to measure temperature. We would not ignore a temperature of 103°F; why should we ignore a pain intensity rating of 8? The Joint Commission for the Accreditation of Healthcare Organizations (JCAHO)standards for pain assessment and management create an expectation that pain be controlled in patients throughout the continuum of healthcare. These standards, to first be scored for compliance in 2001, should be viewed as an opportunity for improvement in pain control rather than just a bureaucratic mandate.32 ASSESSMENT
Effective treatment of pain must first begin with proper assessment. The same principles used for the diagnosis of ischemic heart disease, appendicitis, or renal colic can be applied to the assessment of pain in the palliative care setting. Surveys have indicated that physicians feel that their failure in pain management is linked to their inability to assess pain.63A simple, systematic evaluation such as use of the mnemonic PQRSTU is the answer to the problem. PQRSTU
This mnemonic (modified from Twycross61)can form the basis of any initial and follow-up pain assessment. P stands for precipitating or palliating features: what makes the pain better, and what makes the pain worse. This would include changes in position (i.e., standing, sitting, lying supine), external factors (changesin the weather), and use of nonpharmacologic approaches for control of pain (massage, heat/cold, prayer, or meditation). These features can be determined as part of the history and the physical examination and may guide further diagnostic testing. Q is the quality of the pain: asking the patient to describe in his or her own words what the pain feels like. Somatic pain is pain in skin, muscle, or bone and may be described as aching, stabbing, throbbing, and pressure. Visceral pain is in the organs or viscera and may be described as gnawing, cramping, aching, and sharp. Neuropathic pain is caused by nerve damage and may be described as sharp, burning, stinging, shooting, and tingling. Quality descriptors can help to distinguish nociceptive pain (generally responsive to opiates and anti-inflammatory analgesics) from neuropathic pain (lessresponsive to these agents and may require the use of an adjuvant analgesic, such as a tricyclic antidepressant or anticonvulsant).
X is the region (location) of pain and any referred areas. This can be useful information to guide diagnostictesting. The surgeon is familiar with this portion of assessment from diagnosing appendicitis (periumbilical pain) or gallbladder disease (right shoulder tip pain). S is severity of pain. Typically, the patient is asked to rank the intensity of his or her pain using a numerical scale of 0 to 10, with 0 meaning no pain and 10 meaning pain as bad as imaginable. Ranking of pain intensity is not an adequate assessment by itself, but it serves as a trigger for treatment, especially when the rating is high (> 7). Severity rankings can guide the titration of agents during reassessment for pain relief. T is the temporal nature of the pain. Patterns of pain that occur or worsen at specific times of the day or that may be associated with activity or the end of a dose of medication can guide individualization of dosage and schedule of medication. U stands for medications utilized.Obtaining a through medicationhistory about response to current or previous agents, including analgesic efficacy, allergy and intolerance, and a current list of medications can prevent repeating former mistakes. The treatment of pain should not be delayed for the final diagnosis of the patient's disease or determination of the cause of pain. Experience in the acute pain setting demonstrates that the administration of analgesia to patients with suspected appendicitis does not interfere with the diagnosis of that ~ o n d i t i o n . ~ ~ In addition to the physical component of pain, the assessment should include the psychologic, social, and spiritual ramifications of the patient's pain and disease. Ongoing descriptions of pain unresponsive to medications may in fact be unrecognized depression or existential distress. Pain serves as a gateway to a thorough whole patient assessment for other symptoms that coexist and must be treated simultaneouslyin order for analgesics to be effective. In the same way the surgeon is not in the operating room alone while performing surgery, there are many resources to call on for assistance for this difficult problem. Assessment of the other spheres of pain (psychologic, social, spiritual) requires the surgeon to seek help from other members of the healthcare team, including the nurse, social worker, pharmacist, chaplain, physical therapist, and occupational therapist. Additionally, remember the other important part of the team is the patient's family; their insights to the patient as a person are invaluable. TREATMENT
Pain must be thought of not as a sensation but as a perception. It is a perception as unique as our fingerprints. Tailoring therapy must then be individualized for each patient. Choosing an agent for treating pain can sometimes appear to be a daunting task, especially with so many choices. Pharmacologic management of pain in the palliative care setting can be conceptualized along the three steps of the World Health Organization's (WHO) "analgesic ladder" originally developed for cancer paid7 (Fig. 1). This algorithm bases the selection of an analgesic on the patient's report of
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Step 3, Severe Pain WAS 7-10) Morphine Hvdromomhone ~eitan~l Methadone Levorphanol Nonopioid analgesics Adjuvants
+ +
Step 2, Moderate Pain WAS 4-61 Hydrocodone Oxycodone Dihydrocodeine +Adjuvants -
Step 1,Mild Pain WAS 1-31 Aspirin (ASA) Acetaminophen (Acet) Nonsteroidal anti-inflammatory drugs (NSAIDs) Adjuvants
+
Figure 1. The World Health Organization (WHO) three-step ladder. VAS = visual analog scale.
pain intensity and that adjuvant analgesics are used whenever necessary. These principles are endorsed in other pain guidelines a ~ a i l a b l e . ~ , ~ ~ It is easiest to become familiar with two or three agents in each analgesic category and learn to use them well. This provides the surgeon with the necessary tools to effectively manage pain in greater than eighty percent of cases.68In addition to the severity of the pain, the choice of analgesic may be governed by the patient's description of pain, comorbidities, concomitant therapies, and financial resources. Nonopioid Analgesic Agents
The nonopioid analgesics may be used alone for the treatment of mild to moderate pain (step Ij and in combination with an opioid analgesic in the treatment of moderate to severe pain (stepsI1 and 111).Unlike the opioid analgesics, these drugs have a ceiling dose for analgesia, which surpassing will not produce greater analgesia but increases the risk for toxicity. Acetaminophen The analgesic and antipyretic properties of acetaminophen appear to be mediated by inhibition of prostaglandin production within the central
nervous s y ~ t e m . Unlike ~~,~~ the nonsteroidal anti-inflammatory drugs (NSAIDs), acetaminophen does not cause gastric or renal complications and should be considered first, especially for the treatment of mild to moderate pain. Acetaminophen does not possess any anti-inflammatory effect so it will be less effective in the treatment of inflammatory conditions such as bone pain. The maximum daily dose of acetaminophen should not exceed 4 grams/day to avoid potential hepatic This is especially important in patients receiving fixed combination analgesics (i.e., Tylenol with Codeine, Vicodin, Percocet) and those using over-thecounter cold and cough preparations that contain acetaminophen, along with patient's ordered as needed dosing of acetaminophenfor headaches or fever. Salicylates and Nonsteroidal Anti-inflammatory Drugs These compounds have antipyretic, analgesic, and anti-inflammatory properties. This action is caused by inhibition of cyclooxygenase (isoenzymes COX-1 and COX-2) thereby blocking the biosynthesis of prostaglandins, inflammatory mediators that sensitize peripheral nocicept~rs.~~ This nonselective inhibition of cyclooxygenase activity is also responsible for the majority of the side effects seen with these agents. One agent is not clearly superior over another regarding analgesia. Selection is empiricwith an emphasis on choosing an agent with low risk of toxicity and on the patient's prior response. The use of NSAIDs for patients with renal insufficiency, congestive heart failure, cirrhosis, and history of previous peptic or duodenal ulcer would best be avoided. The elderly are at high risk from the side effects of NSAIDS.~~ Nonacetylated salicylates, such as choline magnesium trisalicylate or salsalate and the selective COX-2 inhibitors, do not inhibit platelet function and may be safer agents in patients at high risk for bleeding or ulcer formation.
Principles of Opioid Use Unlike the postoperative situation where pain is intermittent and often self-limited in nature, pain in the palliative care setting is generally continuous and requires a different approach to management. The traditional approach of as needed dosing is ineffective in patients with continuous chronic pain. This situation calls for a fixed around the clock schedule of medication to prevent pain rather than react to it. The initial treatment of pain and subsequent titration of opioids in an opioid-na'ive patient should be accomplished with the use of immediate-release opioid preparation^.^' Small doses of an analgesic are given on a fixed around the clock schedule to prevent pain. Additional as needed doses are available on a flexible schedule to be used for rescue dosing during intermittent (breakthrough and incident) pain. This would be similar to using a patient-controlled analgesia pump for postoperative pain with a continuous infusion combined with as needed dosing for titration. In determining which opioid to use for pain, it is first useful to discuss which agents to avoid.
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Propoxyphene Propoxyphene is found most commonly in Darvon Compound and Darvocet N-100. A structural analog of methadone, it possesses weak analgesic properties. Analysis of propoxyphene efficacy alone is less active, and when combined with acetaminophenit is no more active than a 200 mg dose of ibuprofen in postoperative pain.41In addition, propoxyphene is metabolized to norpropoxyphene which accumulates with repetitive dosing because of its long half life. Norpropoxyphene is potentially cardiotoxic and a central nervous system irritant with excitatory effects that include tremulousness, dizziness, and seizure^.^^,^^ The combination product Darvocet contains 650 mg of acetaminophen. Greater than six tablets per day places the patient at risk for chronic hepatic toxicity and limits the ability to titrate the drug for pain relief, making it a poor choice. Codeine Codeine is a commonly used opioid analgesic for the management of mild to moderate pain. It is often combined with acetaminophen (Tylenol #3) for a synergistic effect. Codeine would appear to have a limited role in chronic dosing because of increased side effects at doses greater than 1.5 r n g / k g / d ~ s e Codeine .~~ is biotransformed in the liver by the CYP2D6 isoenzyme of the P450 system to morphine to produce part of its analgesic effect. Deficiency in (8%-10% of African American patients, 7% of white patients) and patients on inhibitors of CYP2D6, such as quinidine, cimetidine, or fluoxetine, may prevent the conversion of codeine into morphine, thereby limiting the pain relief from codeine.18 Fixed Combination Products Surgeonshave significantexperience with these agents. Like propoxyphene and codeine, hydrocodone is commercially available with acetaminophen. Oxycodone is commercially available in fixed combinations with acetaminophen or aspirin. These agents are especially useful for mild to moderate pain, but their role in severe pain is limited because of the toxic effects of high doses of the nonopioid. In the case of Percocet or Percodan, the clinician may want to initiate therapy with oxycodone alone, which then can be titrated to effect. The nonopioid (aspirin or acetaminophen) could then be given as a separate agent on a time contingent basis at the maximum daily dose for synergy. Unfortunately, there is no single entity hydrocodone product available in the United States, so if a product like Vicodin or Lortab is used initially, a switch to an alternative opioid needs to occur when the daily limit of acetaminophen (4 g/day) is reached. Meperidine Meperidine (Demerol)is an opioid with a short half-life and short duration of analgesic effect (-3 hours) requiring repetitive dosing to produce sustained analgesia. Meperidine undergoes biotransformation in the liver to normeperidine, which is an active metabolite that is twice as potent a
convulsant and one half as potent an analgesic as meperidine. Accumulation of normeperidine occurs after repetitive dosing and can produce a wide spectrum of central nervous system effects from subtle mood effects, Normeperidine actremors, multifocal myoclonus, and cumulation occurs in patients with renal impairment or the elderly but it has also been noted to occur in patients with normal renal function.29The oral to parenteral ratio for meperidine is high (300 mg orally: 75 mg intravenously) requiring a significant amount of tablets to be taken per dose. All of these factors combine to make meperidine a poor analgesic choice in the palliative care setting. Agonist-Antagonist Agents
The mixed opioid agonist-antagonists, such as pentazocine, butorphanol, nalbuphine and dezocine, are poor choices for analgesia in the palliative care setting. With the exception of pentazocine, oral formulations are not available. Dosing of these agents is limited by a ceiling effect and their use in a patient already receiving an opioid agonist (e.g., morphine) is contraindicated. This combination may cause the opioid to be displaced from the receptor site precipitating an abstinence syndrome manifested by tachycardia, hypertension, diaphoresis, piloerection, nausea and vomiting, diarrhea, body aches, abdominal pain, psychosis, and hallucinations. Pentazocine and butorphanol in particular are associated with a significant degree of psychotomimetic effects.1° The opioids useful for severe pain include morphine (MS Contin, Oramorph, Kadian, Roxanol), hydromorphone (Dilaudid), fentanyl (Duragesic), oxycodone (Roxicodone, Oxycontin), levorphanol (LevoDromoran), oxyrnorphone (Numorphan), and methadone (Dolophine). There can be substantial individual variation in the response to different opioids. Sequential trials of different opioid drugs may be needed to identify the agent that provides the most favorable balance between analgesia and side effect^.^^,^^ Switching between oral and parenteral routes and calculation of a dose is accomplished by understanding the relative potency of each opioid (Table 1).It is important to realize that this is simply a guide; these should not be viewed absolute values. This is in part because of the incomplete cross-tolerance that occurs between drugs. Individualization of the dose of an opioid through careful dose titration provides the basis for success in opioid therapy. The goal is to identify a dose that produces a favorable balance between analgesia and side effects; this is generally accomplished by incremental adjustments of dose. There is no limit to dose escalations during titration as long as untreatable or unmanageable side effects do not appear. Occasionally, patients require hundreds of milligrams of morphine equivalents per day to have effective pain relief.15 Morphine
Morphine is the drug of choice for management of moderate to severe opioid-responsive pain. It is available in multiple formulations, can be given by multiple routes, and extensive clinical experience exists for its use in cancer pain.
Table 1. OPIOID AGONIST DRUGS: RELATIVE POTENCY Drug
Codeine Oxycodone Morphine Hydromorphone Oxymorphone Levorphanol Methadone Meperidine Fentanyl Transdermal System
Duration of Action (h)
Comments
IM (mg)
By Mouth (mg)
130 15*
200 20-30
2-3 2-3
2 4 2 4
10
30
2-3
2 4
1.5-3 1 2 acute 1chronic 20 acute 1-3 chronic 75
7.5 1O(PR) 4 acute 1chronic 10 acute 2-6 chronic 300
2-3 2-3 12-15
2-4 3-4 4-8
Titration limited by nonopioid Use as single entity, sustained release formulation available Sustained release formulations available, avoid use in renal impairment Also available in 3 mg suppository No oral formulation Delayed toxicity possible because of accumulation
15-190
4-8
Delayed toxicity possible because of accumulation
2-4
Listed for reference only, unsuitable agent for use >48 h. Do not use in patients with renal failure or receiving MA0 inhibitors. Patches available in 25,50,75, and 100 ~ g / h strengths. Must use immediate release preparation of another opioid for breakthrough pain.
Half-life (h)
2-3 Transdermal fentany15" 25 pg/h % 60 ~ g / day PO morphme
* Not available in the United States. IM = intramuscular; MA0 = monamine oxidase; PR = per rectum. Datafrom references 3,4a, and 9a.
48-72
The oral route of administration remains the most appropriate for the majority of palliative care patients. Typically, an opioidAnafvepatient is initiated on an immediate release preparation of morphine at a dose of 30 mg orally every four hours around the clock.31A rescue dose can be calculated on 10% to 15% of total dailv dose: in this examvle it would be 20 to 30 mg every one to two hours as nLeded fbr breakthrouihpain.12There are no predictive indicators of dose or plasma concentration for analgesia; the dose must be individualized. Reassessment becomes the critical step to successful analgesic therapy. This begins by quantifying the analgesl'c response to the dose of a given drug, including the degree of pain relief (reduction in pain intensity), duration of response, and need for rescue do sin^. The rescue dosing provides the means for dose titration. Increases in thevdaily maintenance;? around the clock dosing should be considered for patients that require more than 2 to 4 rescue doses per 24-hour period. For example, if the patient is taking 180 mg of oral morphine per day, and requires three 20-mg rescue doses (60mg), this amount should be added to the total daily dose (now 240 mg). The new daily dose can then be divided into an every 4-hour dosing schedule, 40 mg orally every 4 hours around the clock (final dose is dictated by dosage forms available).Changing to a new maintenance dose generally requires that the rescue dose be proportionally increased. Once eood vain relief is achieved with a stable around the clock dose of an immGdiati release opioid, patients may be switched to a sustained release preparation. MS Contin or Oramorph are typically dosed on an 8or 12-hour schedule (in the previous example this would be 120 mg orally every 12hours or 80 mg every 8hours). Kadian is a once-a-day preparation. The advantages to using these products include less blood level variations in comparison to immediate release opioids and fewer dosage units of medication to take on a daily basis, which generally leads to increased patient compliance. Formulary availability and cost generally dictate the choice of a sustained release preparation. These products are not therapeutically interchangeable because of their unique delivery characteristics, so it is best to pick one product and stay with the same product for each individual patient. Morphine is biotransformed in the liver to two glucuronide metabolites, both of which are excreted by the kidneys. Morphine-3-glucuronide (M3G)is the major metabolite and possesses no analgesic properties but has been shown to be responsible for toxicities such as hyperalgesia/allodynia and myoclonus.ll Morphine-6-glucuronide (M6G) binds to opioid receptors to produce analgesic effects; however, data suggest that accumulation of this metabolite may also produce toxicity in patients with renal impairment.28, 45 This suggests that an alternative opioid should be used in patients with moderate to severe renal impairment. Oxycodone
Oral oxycodone has a high oral bioavailability (60%) and analgesic potency comparable to morphine.53As a single entity, it can be titrated
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like morphine to effectively control severe pain.24It is available as a single entity 5-mg tablet, as a sustained release preparation (Oxycontin) dosed every 8 or 12 hours, and a liquid concentrate (20 mg/mL) for patients who have difficulty swallowing. Like morphine, the immediate release preparation should be dosed every 4 hours around the clock for continuous pain. There appears to be no appreciable accumulation of oxycodone's metabolites in patients with significant renal compromise. In this clinical situation oxycodone would be the preferred oral opioid to use. Hydromorphone Hydromorphone (Diluadid) can be administered by the oral, rectal, and parenteral routes. It has the same versatility as morphine. High oral dosing is limited by the tablet strengths currently available and necessity to take every 4 hours. A sustained release oral preparation is currently under development. It may be a useful substitute in patients who do not tolerate morphine because of side effects, especially when the parenteral route of administration is necessary. It is available in a high-concentration preparation (10 mg/mL) and has been shown to have a high bioavailability by continuous subcutaneous infusion (78%).43 Fentanyl Duragesic is a transdermal formulation of fentanyl that delivers 25, 50, 75, or 100 pg per hour as sustained-release opioid. When administered transdermally, the drug accumulates in the subcutaneous adipose which produces sustained concentrations of the drug in the bloodstream. The dosing interval for each system is every 72 hours, but interindividual variability exists, with some patients requiring a dosing interval of every 48 hours.52Indications for the transdermal route would include the unavailability of the oral route, poor compliance, or intolerable side effects associated with other opioids. Patients that are best suited for this delivery system are patients with fairly constant levels of pain.47In patients with rapidly escalating pain or patients at the end of life where the oral route is no longer available, parenteral administration of opioids would be preferred. Because of the delay in peak onset of analgesia after initial application (-20 hours), provisions for breakthrough doses of an immediate release opioid should be available by the oral, rectal, or parenteral route. Adjuvant Agents Adjuvant agents are drugs that are used to control side effects induced by analgesics (i.e., laxatives for constipation, antiemetics for nausea and vomiting) or have analgesic properties themselves. Drugs that have been identified as adjuvant analgesics are principally used to treat neuropathic pain. The applications of these agents in the palliative care setting are based on clinical studies in neuropathic pain states such a diabetic neuropathy or postherpetic neuralgia. Table 2 lists some common adjuvant analgesics
Table 2. ADJUVANT ANAGLESICS Drug
Starting Doses
Comments
Dexamethasone
1-2 mg orally twice a day
Amitriptyline
10-25 mg orally at bedtime
Gabapentin
100 mg orally three times a day
Metastatic bone pain, hepatic capsular distention: high dose (100 mg) for spinal cord compre~sion~~ Slowly titrate to analgesia--consider secondary arnines (desipramineor n~rtriptyline)~" if patient is bothered by anticholinergicside effects. Selective serotonin re-uptake inhibitors have poor efficacy for neuropathic pain42 Increase by 300 mg increments to analgesia, maximum dose of 3600 mg per day54
to consider for patients with pain refractory or only partially responsive to opioid therapy; detailed reviews on neuropathic pain are available.64, 65 Side Effects
Side effect management is an essential element of opioid therapy. Appropriate management of the following side effects can ensure that dose titration of the opioid can continue to doses high enough to produce effective analgesia. Constipation Constipation is the most common side effect seen with opioids and is a common occurrence in the palliative care setting.l6rZ3 Opioids induce constipation by decreasing intestinal motility and increasing anal sphincter tone, creating dried, hard stool that is difficult to evacuate. Survey data suggest that the transdermal fentanyl system (Duragesic) may cause less constipation than oral morphine.20Clinically, there appears to be no difference in the ability to cause constipationfrom one oral opioid to another one. The elderly are especially prone to constipation. It may be associated with abdominal pain and distention, nausea and vomiting, urinary retention, and cognitive impairment, leading to a decrease in the quality of life.8 Success in managing this side effect begins with understanding that tolerance to the constipating effects of opioids rarely develops. Constipation must be anticipated and treated prophylactically. Laxatives are to be titrated to the degree of constipation in the same way opioids are titrated to the severity of pain. The goal should be for comfortable defecation without a set frequency of bowel movements irrespective of prior bowel habits. Stool softeners are often ineffective alone in overcoming opioid effects on the bowel; a stimulant laxative (senna or bisacodyl) combined with oral hydration (if possible) is needed routinely. Osmotic laxatives (lactulose, sorbitol, or a magnesium containing product) can be added if needed. Constipation is a common reason for poor patient compliance with analgesic therapy. Patient and family education coupled with careful attention to bowel habits increases the chances for successful analgesic outcomes.
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Nausea and Vomiting Nausea and vomiting is commonly noted as an "allergy" in patient records. While not an allergy, nausea and vomiting is not as frequent a side effect as often believed, with an incidence estimated from 10% to 40%.9These effects are caused by opioid stimulation of the medullary chemoreceptor trigger zone (CTZ), increased vestibular sensitivity, and increased gastric antral tone. Tolerance to this effect develops quickly, so the prophylactic use of an antiemetic is not generally recommended. If this is a persistent problem, however, scheduled antiemetics may be helpful (e.g., Compazine 10 mg orally before meals and at bedtime) to allow tolerance to develop over the course of several days, after which a trial of withdrawing the antiemetic should occur. If nausea and vomiting persists, rotation to an alternative route (transdermal or parenteral) or alternative opioid would be indicated. Sedation Sedation is a common occurrence after initiation of o ~ i o i dtheravv or after dose escalation.In a patient who has had a long perioi of uncont;dled pain, exhaustion because of sleep deprivation is common. Long periods of sleeping after adequate analgesia has been achieved should not be considered caused by excessive opioid. The patient is catching up on much needed rest; pain is a powerful stimulus to keep us awake. If the patient is aroused easily, then the dose of opioid should not be reduced. Tolerance to sedation usually develops, but in some patients this may be a persistent side effect. Managing this problem begins with reviewing the medications that the patient is on and eliminating unnecessary central nervous system depressant medications. If pain relief is good, dose reduction can be attempted. If pain relief is unsatisfactory or pain reoccurs with dosage reduction, a psychostimulant can be added to the therapy. Methylphenidate (Rtalin) 5 to 10 mg at breakfast and lunch6with doses of up 20 mg twice daily may be used.'j4 Respiratory Depression Respiratory depression is a commonly feared side effect of opioid therapy. Respiratory depression rarely occurs when opioid doses are carefully titrated, and tolerance rapidly develops to this effect. Significant respiratory depression is seen with other central nervous systems effects including sedation and mental clouding. In the palliative care setting, especially with patients at the end of life, accumulation of opioid (or metabolites)may be the culprit. Withholding a scheduled dose or discontinuing regularly scheduled doses and continuing to have rescue doses available for breakthrough pain may be needed. If the patient is becoming progressively obtunded, cannot be awakened, or has severe respiratory depression, naloxone may be given in smallintravenous injections (0.4mg diluted in 10mL of saline, 1mL given every 1-2 minutes). The dose of naloxone should be sufficient to improve respiration (respiratoryrate > 10 or patient is aroused by
verbal stimuli) but without completely reversing analgesia, which causes severe pain and a withdrawal syndrome.39Naloxone has a short halflife; patients receiving sustained release morphine, sustained release oxycodone, transdermal fentanyl, or methadone may require repeated doses or a naloxone infusion to prevent recurrence of respiratory d e p r e ~ s i o n . ~ ~ Addiction versus Physical Dependence and Tolerance
There continues to be a popular myth that the use of opioids for pain control leads to addiction. This is in part because of confusion about the differences between addiction, physical dependence, and tolerance. Addiction is vsvcholoeic " devendence bn drum " with behavior centering on compulsive drug use (loss of control over drugs, prescriptions from multiple physicians, illegal means of procuring more drugs) and continued use, despite harm. This is a rare outcome of pain management, especially in a patient without a history of substance abuse. In a study of cancer patients who were treated with morphine for a total of 22,525 treatment days, only one patient developed problems related to substance abuse.66 Physical dependence is a process of neuroadaptation resulting from being exposed to exogenous opioids (similar to the effects seen with betablockers or alpha-2 agonists). This is generally seen in all patients taking re~ularlv " ,scheduled doses of ovioids after 7 to 10 davs. Abruvt discontinuation of the opioid may cause an abstinence syndrome characterized by tachycardia, hypertension, diaphoresis,piloerection, nausea and vomiting, diarrhea, body aches, abdominal pain, psychosis, and hallucinations. This by the administration of agonist-antagonist agents may be or by naloxone. This rarely is a clinical problem if patients are warned to avoid abrupt discontinuation and a tapering schedule in employed if opioid therapy is no longer necessary, such as after a neurolytic procedure. Patients currently abusing or with a history of substance abuse can also develop pain. Under-treatment of pain is an issue in these patients, especially AIDS patients, who tend to be younger and disproportionately comprised of substance abuser^.^ These patients deserve attentive treatment that may require consultation with a pain specialist to effectively manage their pain. Tolerance is the reduced effectiveness of a known dose of medication over time. Tolerance to opioid side effects is commonly seen (with the exception of constipation) and is desired. Tolerance to analgesia is rarely seen with continued use of opioids. Patients often have long periods where the dose of opioid needed for pain relief remains stable. Diminished pain relief from a previously effective dose is a clue to the clinician to suspect worsening of the underlying disease instead of tolerance to the opioid. I
-'
SUMMARY
Since the introduction of ether, a multitude of anesthesia and analgesia techniques have been introduced to ensure pain relief for our patients.
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Several surgeons have made lasting contributions to the understanding and treatment of pain. Foremost in this area is Dr William K. Livingston, who chaired the Department of Surgery at the University of Oregon Medical School. In 1943, he published Pain Mechanisms outlining the specificity theory of pain. Pain and Sufeuing, published in 1998, 32 years after his death, describes his experimental and clinical observations as a researcher, clinician, and surgeon.37What is clear in Livingston's writings about his understanding and subsequent treatment of his patients is that everything is centered on the patient's report of pain. A surgeon fulfills his or her responsibility to effective pain management by using this central principle as the guidepost to the care of his or her patient. ACKNOWLEDGMENT The author wishes to acknowledge the assistance of Mary E. Campomizzi, PharmD, in preparing this article.
References 1. American College of Surgeons: Statement on principles guiding care at the end of life. Bulletin of the American College of Surgeons 83:46,1998 2. American Medical Association: First Code of Medical Ethics. Reprinted in Reiser SJ, Dyck AJ, Curran WJ (eds): Ethics in Medicine. Cambridge, MA, MIT Press, 1977 3. American Pain Society: Principles of Analgesic Use in the Treatment of Acute Pain and Cancer Pain, ed 4. Skokie, IL, American Pain Society, 1999 4. Bernabei R, Gambassi G, Lapane K, et al: Management of pain in elderly patients with cancer. JAMA 279:1877-82,1998 4a. Breitbart W, Chandler S, Eagel B, et al: An alternative algorithm for dosing transdermal fentanyl for cancer-related pain. Oncology 14:695-705,2000 5. Breitbart W, Rosenfeld BD, Passik SD, et al: The under-treatment of pain in ambulatory AIDS patients. Pain 65:243-249,1996 6. Bruera E, Brenneis C, Paterson AH, et al: Use of methylphenidate as an adjuvant to narcotic analgesics in patients with advanced cancer. J Pain Symptom Manage 4:3-6,1989 7. Bruera E, Roca E, Cedaro L, et al: Action of oral methylprednisolone in terminal cancer patients: A prospective randomized double-blind study. Cancer Treat Rep 69:751-754, 1985 8. Bruera E, Suarez-Almazor M, Velasco A, et al: The assessment of constipation in terminal cancer patients admitted to a palliative care unit: A retrospective review. J Pain Symptom Manage 9:515,1994 9. Campora E, Merlini L, Pace M, et al: The incidence of narcotic induced emesis. J Pain Symptom Manage 6:428-430,1991 9a. Chemv NI: The manaeement of cancer vain. CA Cancer T Clin 50:78,2000 10. ~ h e r n ;NI: Opioid an&esics: ~ompa&tivefeatures and guidelines. Drugs 51:713-737,1996 11. Christru~LL: Morvhine metabolites. Acta Anaesthesiol Scand 41:116-122.1997 12. cleary J*: Cancer i a i n management. Cancer Control 7:120-131,2000 13. Cleeland CS, Gonin R, Hatfield AK, et al: Pain and its treatment in outpatients with metastatic cancer. N Engl J Med 330:592-6,1994 14. Council on Ethical and Judicial Affairs, American Medical Association: Decision near the end of life. JAMA 267:229-233,1992 15. Coyle N, Adelhardt J, Foley KM, et al: Character of terminal illness in the advanced cancer patient: Pain and other symptoms during the last four weeks of life. J Pain Symptom Manage 5:83-93,1990
16. Curtis EB, Krech R, Walsh TD: Common symptoms in patients with advanced cancer. J Palliat Care 7:25,1991 17. Desbiens NA, Wu AW. Pain and suffering in seriously ill hospitalized patients. J Am Geriatr Soc 48:S183-S186,2000 18. Desmeules J, Gascon MP, Dayer P, et al: Impact of environmental and genetic factors on codeine analgesia. Eur J Clin Pharmacol41:23-6,1991 19. De Stoutz ND, Bruera E, Suarez-Almazor M: Opioid rotation for toxicity reduction in terminal cancer patients. J Pain Symptom Manage 10:378-384,1995 20. Donner B, Zenz M, Tryba M, et al: Direct conversion from oral morphine to transdermal fentanyl: A multicenter study in patients with cancer pain. Pain 64527-534,1996 21. Eisendrath SJ, GoldmanB, Douglas J, et al: Meperidine-induced delirium. Am JPsychiatry 144:1062-1065,1987 22. Galer BS, Coyle N, Pasternak GW, et al: Individual variability in the response to different opioids: Report of five cases. Pain 49:87-91,1992 23. Glare P, Lickiss JN: Unrecognized constipation in patients with advanced cancer: A recipe for therapeutic disaster. J Pain Symptom Manage 7:369,1992 24. Glare PA, Walsh TD. Dose-ranging study of oxycodone for chronic pain in advanced cancer. J Clin Oncol11:973-978,1993 25. Goldfrank L, Weisman RS, Errick JK, et al: A dosing nomogram for continuous infusion intravenous naloxone. Ann Emerg Med 15:566-570,1986 26. Grond S, Zech D, Diefenbach C, et al: Prevalence and pattern of symptoms in patients with cancer pain. A prospective evaluation of 1635cancer patients referred to a pain clinic. J Pain Symptom Manage 9:372-82,1994 27. Grossman SA, Benedetti C, Payne R, et al: NCCN practice guidelines for cancer pain. Oncology 133344,1999 28. Hagen NA, Foley KM, Cerbone DJ, et al: Chronic nausea and morphine-6-glucuronide. J Pain Symptom Manage 6:125-128,1991 29. Hagmeyer KO, Mauro LS, Mauro VF: Meperidine-related seizures associated with patient-controlled analgesia pumps. Ann Pharmacother 27:29-32,1993 30. Inturrisi CE, Colbum WN, Verebey K, et al: Propoxyphene and norpropoxyphene kinetics after single and repeated doses of propoxyphene. Clin Pharmacol Ther 31:157-167, 1982 .31. Jacox A, Carr DB, Payne R, et al: Management of Cancer Pain. AHCPR Publication No. 94-0592: Clinical Practice Guideline No. 9. Rockville, MD: U.S. Department of Health and Human Services, Public Health Service, March 1994 32. Joint Commission on Accreditation of Healthcare Organizations: Pain assessment and management standards 1999. Available at www.jcaho.org/standard/pm~coll.html 33. Kaiko RF, Foley KM, Grabinski PY, et al: Central nervous system excitatory effects of meperidine in cancer patients. Ann Neurol13:180-5,1983 34. Kassirer MR, Osterberg DH: Pain in chronic multiple sclerosis. J Pain Symptom Manage 295-97,1987 35. Kingery WS: A critical review of controlled clinical trials for peripheral neuropathic pain and complex regional pain syndromes. Pain 73:123-139,1997 36. Levy MH: Pharmacologic treatment of cancer pain. N Engl J Med 335:1124-1132,1996 37. Linvingston WK: Pain and Suffering. Seattle, IASP Press, 1998 38. Malmberg AB, Yaksh TL: Hyperalgesia medicated by spinal glutamate and substance P receptors blocked by spinal cyclooxygenaseinhibition. Science 923276-1279,1992 39. Manfredi PL, Ribeiro S, Chandler SW, et al: Inappropriate use of naloxone in cancer patients with pain. J Pain Symptom Manage 11:131-134,1996 40. Max MB, Kishore-Kumar R, Schafer SC, et al: Efficacy of desipramine in painful diabetic neuropathy: A placebo-controlled trial. Pain 45:3-9,1991 41. Dextropropoxyphene in postoperative pain. In McQuay H, Moore A (eds): An EvidenceBased Resource for Pain Relief. Oxford, Oxford University Press, 1998, pp 132-137 42. McQuay HJ, Tramer M, Nye BA, et al: A systematic review of antidepressants in neuropathic pain. Pain 68:217-227,1996 43. Moulin DE, Kreeft JH, Murray PN, et al: Comparison of continuous subcutaneous and intravenous hydromorphone infusions for management of cancer pain. Lancet 337:465468,1991 -
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44. Oliver D: The quality of care and symptom control-the effects on the terminal phase of ALS/MND. J Neurolog Sciences 139:134-136,1996 45. Osborne R, Joel S, Grebenik K, et al: The pharmacolunetics of morphine and morphine glucuronides in kidney failure. Clin Pharmacol Ther 54:158-167,1993 46. Pace S, Burke TF: Intravenous morphine for early pain relief in patients with acute abdominal pain. Acad Emerg Med 3:1086-1092,1996 47. Payne R, Chandler S, Einhaus M. Guidelines for the clinical use transdermal fentanyl. Anticancer Drugs 6(suppl):50-53,1995 48. Perry S, Heidrich G: Management of pain during dkbridement: a survey of US burn units. Pain 13:267-280,1982 49. Phillips AC, Polisson RP, Simon LS: NSAIDs and the elderly: Toxicity and economic implications. Drugs Aging 10:119-30,1997. 50. Piletta P, Porchet HC, Dayer P: Central analgesiceffect of acetaminophenbut not of aspirin. Clin Pharm Ther 49:350-354,1991 51. Portenoy RK: Pharmacologic management of cancer pain. Semin Oncol22:112-120,1995 52. Portenoy RK, Southam M, Gupta SK, et al: Transdermal fentanyl for cancer pain: Repeated dose pharmacokinetics. Anesthesiology 78:3643,1993 53. Poyhia R, Vainio A, Kalso E: A review of oxycodone's clinical pharmacokinetics and pharmacodynamics. J Pain Symptom Manage 8:63-67,1993 54. Rowbotham M, Harden N, Stacey B, et al: Gabepentin for the treatment of postherpetic neuralgia. JAMA 280:1837-1842,1998 55. Schnitzer TJ: Non-NSAID pharmacologic treatment options for the management of chronic pain. Am J Med 105(Suppl lB):45S-52S, 1998 56. Schug SA, Zech D, Grond S, et al: A long-term survey of morphine in cancer pain patients. J Pain Symptom Manage 7:259-266,1992 57. Sindrup SH, Jensen TS. Efficacy of pharmacological treatments of neuropathic pain: an update and effect related to mechanism of drug action. Pain 83:389-400,1999 58. Sorensen, S, Helweg-Larsen S, Mouridsen H, et al: Effect of high-dose dexamethasone in carcinomatous metastatic spinal cord compression treated with radiotherapy: A randomized trial. Eur J Cancer 30A:22-27,1994 59. Szeto HH, Intrurrisi CE, Houde R, et al: Accumulation of normeperidine, an active metabolite of meperidine, inpatients with renal failure or cancer.Ann Intern Med 86:738741,1977 60. The SUPPORT Principal Investigators: A controlled trial to improve care for seriously ill hospitalized patients. JAMA 274:1591-1598,1995 61. Twycross RG: Pain and analgesics. Curr Med Res Opin 5:497-505,1978 62. Vane JR, Botting RM: Anti-inflammatory drugs and their mechanism of action. Inflamm Res 47:S78-S87,1998 63. Von Roenn JH, Cleeland CS, Gonin R, et al: Physician attitudes and practice in cancer pain management. Ann Intern Med 119:121-126,1993 64. Walsh D: Pharmacological management of cancer pain. Semin Oncol27:45-63,2000 65. Whitcomb DC, Block GD: Association of acetaminophen hepatotoxicty with fasting and ethanol use. JAMA 272:1845-1850,1994 66. Wolfe J, Grier HE, Klar N, et al: Symptoms and suffering at the end of life in children with cancer. N Engl J Med 342326-33,2000 67. World Health Organization: Cancer Pain Relief and Palliative Care: Report of a WHO Expert Committee (ed 3). Geneva, World Health Organization, 1996 68. Zech DFJ, Grond S, Lynch J, et al: Validation of World Health Organization guidelines for cancer pain relief: A 10-year prospective study. Pain 63:65-76,1995
Address reprint requests to James B. Ray, PharmD Department of Pharmacy and Drug Information Services Hamot Medical Center 201 State Street Erie, PA 16550
1055-3207/01 $15.00
+ .OO
PHARMACOLOGIC MANAGEMENT OF PAIN The Surgeon's Responsibility James B. Ray, PharmD
Divinum est sedare dolorem-Blessed
are those w h o treat pain. GALEN
Historically surgeons have had to witness their patients' pain probably longer than any specialty within medicine. Until the mid 1800s, in attempts to provide lasting relief from disease, surgeons were required to operate on their fellow man without the aid of anesthesia. In 1846, the same year the first surgical procedure with ether was performed, the American Medical Association's (AMA)First Code of Medical Ethics stated, "A physician ought not to abandon a patient because the case is deemed incurable; for his attendance may continue to be highly useful to the patient, comforting to the relatives around him, even in the last period of a fatal malady, by alleviating pain and other symptoms, and by soothing mental anguish.'12 More recently the AMA stated, "Physicians have an obligation to relieve pain and suffering and to promote the dignity and autonomy of dying patients in their care."14 Embodied within the American College of Surgeons statement on principles guiding care at the end of life is the principle to "ensure alleviation of pain and management of other physical symptoms."' Pain relief in palliative care forms the cornerstone of a comprehensive pattern of care that encompasses the physical, psychologic, social, and spiritual aspects of suffering. From the Department of Pharmacy and Drug Information Services, Hamot Medical Center, Erie, Pennsylvania
SURGICAL ONCOLOGY CLINICS OF NORTH AMERICA VOLUME 10. NUMBER 1 .JANUARY 2001
71
Pain is a common feature in cancer. Thirty to forty percent of patients have pain at the time of diagnosis, and 65% to 85% have pain in the advanced stages of their i l l n e s ~ . ~Pain ~,~ also ~ , commonly ~~ occurs in other progressive malignant (noncancer) diseases such as AIDS, multiple scle~ ~ , from the SUPPORT and rosis, and amyotrophic lateral s c l e r ~ s i s .44~ ,Data HELP studies indicate that pain is often severe in seriously ill and elderly patients and patients with conditions that are not often thought to be associated with pain, such as chronic obstructive pulmonary disease, congestive heart failure, and cirrhosis.17 Pain continues to be universally under-treated in every area of healthcare.4,5,13,60,66 In a society that lives by mottoes such as "no pain, no gain" and "just say no to drugs," pervasive subconscious barriers to effective pain relief exist. In being responsible for effective pain management to the patient, the surgeon must first set aside his or her own beliefs and attitudes regarding pain and its control and be open to change. PAIN PATHOPHYSIOLOGY
Pain can be acute or chronic. Acute pain has a beginning and an end, and is linked to iatrogenic or accidental tissue damage. This type of pain diminishes and resolves within days to weeks of tissue healing. Chronic pain cannot always be clearly related to any known tissue damage. The patient often has no clear recollection of when it began and at times, death may seem the only solution to end his or her pain. Acute and chronic pain may be of a nociceptive or neuropathic origin. The perception of nociceptive pain is caused by direct stimulation of intact mechanical, chemical, or thermal nociceptors and transmission of impulses along normal functioning nerves. Nociceptive pain can be subdivided into somatic and visceral. Somatic pain describes the stimulation of the nervous system within the skin, soft tissue, muscle, and bone. Common descriptors of somatic pain include "sharp," "aching," and "throbbing," and the pain is often well localized. Visceral pain results from stimulation of the autonomic nervous system associated with the heart, lungs, and gastrointestinal and genitourinary tracts. This pain may be more difficult to describe and localize. Both types of nociceptive pain usually respond to opioids and anti-inflammatoryagents. Neuropathic pain is believed to be caused by dysfunction of the peripheral or central nervous system. Common syndromes of neuropathic pain include phantom pain, postherpetic neuralgia, and malignant plexopathies. Patients often describe this type of pain with words like "burning," "tingling," "numbness," "shooting," "stabbing," or "electric-like feelings." Neuropathic pain may respond to opioids, but often a combination of opioids with adjuvant analgesics (tricyclic antidepressants, anticonvulsants, antiarrhythmics) is needed to achieve effective pain control. To be personally accountable for a patient's pain the surgeon must first understand the extent of the problem. Control of postoperative complications like fever or wound dehiscence has paramount importance in
PHARMACOLOGIC MANAGEMENT OF PAIN
73
the surgeon's mind regarding successful outcomes. Because of the impact on physical and psychologic function, poor pain control should be viewed in the same light. Adopting pain as the "fifth vital sign" creates a situation where pain now becomes visible. Assessment and documentation of the intensity of pain along with the other vital signs demands our attention. Using a simple tool to rate the intensity of pain, such as a verbal scale where 0 = no pain and 10 = pain as bad as imaginable, is analogous to using a thermometer to measure temperature. We would not ignore a temperature of 103°F; why should we ignore a pain intensity rating of 8? The Joint Commission for the Accreditation of Healthcare Organizations (JCAHO)standards for pain assessment and management create an expectation that pain be controlled in patients throughout the continuum of healthcare. These standards, to first be scored for compliance in 2001, should be viewed as an opportunity for improvement in pain control rather than just a bureaucratic mandate.32 ASSESSMENT
Effective treatment of pain must first begin with proper assessment. The same principles used for the diagnosis of ischemic heart disease, appendicitis, or renal colic can be applied to the assessment of pain in the palliative care setting. Surveys have indicated that physicians feel that their failure in pain management is linked to their inability to assess pain.63A simple, systematic evaluation such as use of the mnemonic PQRSTU is the answer to the problem. PQRSTU
This mnemonic (modified from Twycross61)can form the basis of any initial and follow-up pain assessment. P stands for precipitating or palliating features: what makes the pain better, and what makes the pain worse. This would include changes in position (i.e., standing, sitting, lying supine), external factors (changesin the weather), and use of nonpharmacologic approaches for control of pain (massage, heat/cold, prayer, or meditation). These features can be determined as part of the history and the physical examination and may guide further diagnostic testing. Q is the quality of the pain: asking the patient to describe in his or her own words what the pain feels like. Somatic pain is pain in skin, muscle, or bone and may be described as aching, stabbing, throbbing, and pressure. Visceral pain is in the organs or viscera and may be described as gnawing, cramping, aching, and sharp. Neuropathic pain is caused by nerve damage and may be described as sharp, burning, stinging, shooting, and tingling. Quality descriptors can help to distinguish nociceptive pain (generally responsive to opiates and anti-inflammatory analgesics) from neuropathic pain (lessresponsive to these agents and may require the use of an adjuvant analgesic, such as a tricyclic antidepressant or anticonvulsant).
X is the region (location) of pain and any referred areas. This can be useful information to guide diagnostictesting. The surgeon is familiar with this portion of assessment from diagnosing appendicitis (periumbilical pain) or gallbladder disease (right shoulder tip pain). S is severity of pain. Typically, the patient is asked to rank the intensity of his or her pain using a numerical scale of 0 to 10, with 0 meaning no pain and 10 meaning pain as bad as imaginable. Ranking of pain intensity is not an adequate assessment by itself, but it serves as a trigger for treatment, especially when the rating is high (> 7). Severity rankings can guide the titration of agents during reassessment for pain relief. T is the temporal nature of the pain. Patterns of pain that occur or worsen at specific times of the day or that may be associated with activity or the end of a dose of medication can guide individualization of dosage and schedule of medication. U stands for medications utilized.Obtaining a through medicationhistory about response to current or previous agents, including analgesic efficacy, allergy and intolerance, and a current list of medications can prevent repeating former mistakes. The treatment of pain should not be delayed for the final diagnosis of the patient's disease or determination of the cause of pain. Experience in the acute pain setting demonstrates that the administration of analgesia to patients with suspected appendicitis does not interfere with the diagnosis of that ~ o n d i t i o n . ~ ~ In addition to the physical component of pain, the assessment should include the psychologic, social, and spiritual ramifications of the patient's pain and disease. Ongoing descriptions of pain unresponsive to medications may in fact be unrecognized depression or existential distress. Pain serves as a gateway to a thorough whole patient assessment for other symptoms that coexist and must be treated simultaneouslyin order for analgesics to be effective. In the same way the surgeon is not in the operating room alone while performing surgery, there are many resources to call on for assistance for this difficult problem. Assessment of the other spheres of pain (psychologic, social, spiritual) requires the surgeon to seek help from other members of the healthcare team, including the nurse, social worker, pharmacist, chaplain, physical therapist, and occupational therapist. Additionally, remember the other important part of the team is the patient's family; their insights to the patient as a person are invaluable. TREATMENT
Pain must be thought of not as a sensation but as a perception. It is a perception as unique as our fingerprints. Tailoring therapy must then be individualized for each patient. Choosing an agent for treating pain can sometimes appear to be a daunting task, especially with so many choices. Pharmacologic management of pain in the palliative care setting can be conceptualized along the three steps of the World Health Organization's (WHO) "analgesic ladder" originally developed for cancer paid7 (Fig. 1). This algorithm bases the selection of an analgesic on the patient's report of
PHARMACOLOGIC MANAGEMENT OF PAIN
75
Step 3, Severe Pain WAS 7-10) Morphine Hvdromomhone ~eitan~l Methadone Levorphanol Nonopioid analgesics Adjuvants
+ +
Step 2, Moderate Pain WAS 4-61 Hydrocodone Oxycodone Dihydrocodeine +Adjuvants -
Step 1,Mild Pain WAS 1-31 Aspirin (ASA) Acetaminophen (Acet) Nonsteroidal anti-inflammatory drugs (NSAIDs) Adjuvants
+
Figure 1. The World Health Organization (WHO) three-step ladder. VAS = visual analog scale.
pain intensity and that adjuvant analgesics are used whenever necessary. These principles are endorsed in other pain guidelines a ~ a i l a b l e . ~ , ~ ~ It is easiest to become familiar with two or three agents in each analgesic category and learn to use them well. This provides the surgeon with the necessary tools to effectively manage pain in greater than eighty percent of cases.68In addition to the severity of the pain, the choice of analgesic may be governed by the patient's description of pain, comorbidities, concomitant therapies, and financial resources. Nonopioid Analgesic Agents
The nonopioid analgesics may be used alone for the treatment of mild to moderate pain (step Ij and in combination with an opioid analgesic in the treatment of moderate to severe pain (stepsI1 and 111).Unlike the opioid analgesics, these drugs have a ceiling dose for analgesia, which surpassing will not produce greater analgesia but increases the risk for toxicity. Acetaminophen The analgesic and antipyretic properties of acetaminophen appear to be mediated by inhibition of prostaglandin production within the central
nervous s y ~ t e m . Unlike ~~,~~ the nonsteroidal anti-inflammatory drugs (NSAIDs), acetaminophen does not cause gastric or renal complications and should be considered first, especially for the treatment of mild to moderate pain. Acetaminophen does not possess any anti-inflammatory effect so it will be less effective in the treatment of inflammatory conditions such as bone pain. The maximum daily dose of acetaminophen should not exceed 4 grams/day to avoid potential hepatic This is especially important in patients receiving fixed combination analgesics (i.e., Tylenol with Codeine, Vicodin, Percocet) and those using over-thecounter cold and cough preparations that contain acetaminophen, along with patient's ordered as needed dosing of acetaminophenfor headaches or fever. Salicylates and Nonsteroidal Anti-inflammatory Drugs These compounds have antipyretic, analgesic, and anti-inflammatory properties. This action is caused by inhibition of cyclooxygenase (isoenzymes COX-1 and COX-2) thereby blocking the biosynthesis of prostaglandins, inflammatory mediators that sensitize peripheral nocicept~rs.~~ This nonselective inhibition of cyclooxygenase activity is also responsible for the majority of the side effects seen with these agents. One agent is not clearly superior over another regarding analgesia. Selection is empiricwith an emphasis on choosing an agent with low risk of toxicity and on the patient's prior response. The use of NSAIDs for patients with renal insufficiency, congestive heart failure, cirrhosis, and history of previous peptic or duodenal ulcer would best be avoided. The elderly are at high risk from the side effects of NSAIDS.~~ Nonacetylated salicylates, such as choline magnesium trisalicylate or salsalate and the selective COX-2 inhibitors, do not inhibit platelet function and may be safer agents in patients at high risk for bleeding or ulcer formation.
Principles of Opioid Use Unlike the postoperative situation where pain is intermittent and often self-limited in nature, pain in the palliative care setting is generally continuous and requires a different approach to management. The traditional approach of as needed dosing is ineffective in patients with continuous chronic pain. This situation calls for a fixed around the clock schedule of medication to prevent pain rather than react to it. The initial treatment of pain and subsequent titration of opioids in an opioid-na'ive patient should be accomplished with the use of immediate-release opioid preparation^.^' Small doses of an analgesic are given on a fixed around the clock schedule to prevent pain. Additional as needed doses are available on a flexible schedule to be used for rescue dosing during intermittent (breakthrough and incident) pain. This would be similar to using a patient-controlled analgesia pump for postoperative pain with a continuous infusion combined with as needed dosing for titration. In determining which opioid to use for pain, it is first useful to discuss which agents to avoid.
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Propoxyphene Propoxyphene is found most commonly in Darvon Compound and Darvocet N-100. A structural analog of methadone, it possesses weak analgesic properties. Analysis of propoxyphene efficacy alone is less active, and when combined with acetaminophenit is no more active than a 200 mg dose of ibuprofen in postoperative pain.41In addition, propoxyphene is metabolized to norpropoxyphene which accumulates with repetitive dosing because of its long half life. Norpropoxyphene is potentially cardiotoxic and a central nervous system irritant with excitatory effects that include tremulousness, dizziness, and seizure^.^^,^^ The combination product Darvocet contains 650 mg of acetaminophen. Greater than six tablets per day places the patient at risk for chronic hepatic toxicity and limits the ability to titrate the drug for pain relief, making it a poor choice. Codeine Codeine is a commonly used opioid analgesic for the management of mild to moderate pain. It is often combined with acetaminophen (Tylenol #3) for a synergistic effect. Codeine would appear to have a limited role in chronic dosing because of increased side effects at doses greater than 1.5 r n g / k g / d ~ s e Codeine .~~ is biotransformed in the liver by the CYP2D6 isoenzyme of the P450 system to morphine to produce part of its analgesic effect. Deficiency in (8%-10% of African American patients, 7% of white patients) and patients on inhibitors of CYP2D6, such as quinidine, cimetidine, or fluoxetine, may prevent the conversion of codeine into morphine, thereby limiting the pain relief from codeine.18 Fixed Combination Products Surgeonshave significantexperience with these agents. Like propoxyphene and codeine, hydrocodone is commercially available with acetaminophen. Oxycodone is commercially available in fixed combinations with acetaminophen or aspirin. These agents are especially useful for mild to moderate pain, but their role in severe pain is limited because of the toxic effects of high doses of the nonopioid. In the case of Percocet or Percodan, the clinician may want to initiate therapy with oxycodone alone, which then can be titrated to effect. The nonopioid (aspirin or acetaminophen) could then be given as a separate agent on a time contingent basis at the maximum daily dose for synergy. Unfortunately, there is no single entity hydrocodone product available in the United States, so if a product like Vicodin or Lortab is used initially, a switch to an alternative opioid needs to occur when the daily limit of acetaminophen (4 g/day) is reached. Meperidine Meperidine (Demerol)is an opioid with a short half-life and short duration of analgesic effect (-3 hours) requiring repetitive dosing to produce sustained analgesia. Meperidine undergoes biotransformation in the liver to normeperidine, which is an active metabolite that is twice as potent a
convulsant and one half as potent an analgesic as meperidine. Accumulation of normeperidine occurs after repetitive dosing and can produce a wide spectrum of central nervous system effects from subtle mood effects, Normeperidine actremors, multifocal myoclonus, and cumulation occurs in patients with renal impairment or the elderly but it has also been noted to occur in patients with normal renal function.29The oral to parenteral ratio for meperidine is high (300 mg orally: 75 mg intravenously) requiring a significant amount of tablets to be taken per dose. All of these factors combine to make meperidine a poor analgesic choice in the palliative care setting. Agonist-Antagonist Agents
The mixed opioid agonist-antagonists, such as pentazocine, butorphanol, nalbuphine and dezocine, are poor choices for analgesia in the palliative care setting. With the exception of pentazocine, oral formulations are not available. Dosing of these agents is limited by a ceiling effect and their use in a patient already receiving an opioid agonist (e.g., morphine) is contraindicated. This combination may cause the opioid to be displaced from the receptor site precipitating an abstinence syndrome manifested by tachycardia, hypertension, diaphoresis, piloerection, nausea and vomiting, diarrhea, body aches, abdominal pain, psychosis, and hallucinations. Pentazocine and butorphanol in particular are associated with a significant degree of psychotomimetic effects.1° The opioids useful for severe pain include morphine (MS Contin, Oramorph, Kadian, Roxanol), hydromorphone (Dilaudid), fentanyl (Duragesic), oxycodone (Roxicodone, Oxycontin), levorphanol (LevoDromoran), oxyrnorphone (Numorphan), and methadone (Dolophine). There can be substantial individual variation in the response to different opioids. Sequential trials of different opioid drugs may be needed to identify the agent that provides the most favorable balance between analgesia and side effect^.^^,^^ Switching between oral and parenteral routes and calculation of a dose is accomplished by understanding the relative potency of each opioid (Table 1).It is important to realize that this is simply a guide; these should not be viewed absolute values. This is in part because of the incomplete cross-tolerance that occurs between drugs. Individualization of the dose of an opioid through careful dose titration provides the basis for success in opioid therapy. The goal is to identify a dose that produces a favorable balance between analgesia and side effects; this is generally accomplished by incremental adjustments of dose. There is no limit to dose escalations during titration as long as untreatable or unmanageable side effects do not appear. Occasionally, patients require hundreds of milligrams of morphine equivalents per day to have effective pain relief.15 Morphine
Morphine is the drug of choice for management of moderate to severe opioid-responsive pain. It is available in multiple formulations, can be given by multiple routes, and extensive clinical experience exists for its use in cancer pain.
Table 1. OPIOID AGONIST DRUGS: RELATIVE POTENCY Drug
Codeine Oxycodone Morphine Hydromorphone Oxymorphone Levorphanol Methadone Meperidine Fentanyl Transdermal System
Duration of Action (h)
Comments
IM (mg)
By Mouth (mg)
130 15*
200 20-30
2-3 2-3
2 4 2 4
10
30
2-3
2 4
1.5-3 1 2 acute 1chronic 20 acute 1-3 chronic 75
7.5 1O(PR) 4 acute 1chronic 10 acute 2-6 chronic 300
2-3 2-3 12-15
2-4 3-4 4-8
Titration limited by nonopioid Use as single entity, sustained release formulation available Sustained release formulations available, avoid use in renal impairment Also available in 3 mg suppository No oral formulation Delayed toxicity possible because of accumulation
15-190
4-8
Delayed toxicity possible because of accumulation
2-4
Listed for reference only, unsuitable agent for use >48 h. Do not use in patients with renal failure or receiving MA0 inhibitors. Patches available in 25,50,75, and 100 ~ g / h strengths. Must use immediate release preparation of another opioid for breakthrough pain.
Half-life (h)
2-3 Transdermal fentany15" 25 pg/h % 60 ~ g / day PO morphme
* Not available in the United States. IM = intramuscular; MA0 = monamine oxidase; PR = per rectum. Datafrom references 3,4a, and 9a.
48-72
The oral route of administration remains the most appropriate for the majority of palliative care patients. Typically, an opioidAnafvepatient is initiated on an immediate release preparation of morphine at a dose of 30 mg orally every four hours around the clock.31A rescue dose can be calculated on 10% to 15% of total dailv dose: in this examvle it would be 20 to 30 mg every one to two hours as nLeded fbr breakthrouihpain.12There are no predictive indicators of dose or plasma concentration for analgesia; the dose must be individualized. Reassessment becomes the critical step to successful analgesic therapy. This begins by quantifying the analgesl'c response to the dose of a given drug, including the degree of pain relief (reduction in pain intensity), duration of response, and need for rescue do sin^. The rescue dosing provides the means for dose titration. Increases in thevdaily maintenance;? around the clock dosing should be considered for patients that require more than 2 to 4 rescue doses per 24-hour period. For example, if the patient is taking 180 mg of oral morphine per day, and requires three 20-mg rescue doses (60mg), this amount should be added to the total daily dose (now 240 mg). The new daily dose can then be divided into an every 4-hour dosing schedule, 40 mg orally every 4 hours around the clock (final dose is dictated by dosage forms available).Changing to a new maintenance dose generally requires that the rescue dose be proportionally increased. Once eood vain relief is achieved with a stable around the clock dose of an immGdiati release opioid, patients may be switched to a sustained release preparation. MS Contin or Oramorph are typically dosed on an 8or 12-hour schedule (in the previous example this would be 120 mg orally every 12hours or 80 mg every 8hours). Kadian is a once-a-day preparation. The advantages to using these products include less blood level variations in comparison to immediate release opioids and fewer dosage units of medication to take on a daily basis, which generally leads to increased patient compliance. Formulary availability and cost generally dictate the choice of a sustained release preparation. These products are not therapeutically interchangeable because of their unique delivery characteristics, so it is best to pick one product and stay with the same product for each individual patient. Morphine is biotransformed in the liver to two glucuronide metabolites, both of which are excreted by the kidneys. Morphine-3-glucuronide (M3G)is the major metabolite and possesses no analgesic properties but has been shown to be responsible for toxicities such as hyperalgesia/allodynia and myoclonus.ll Morphine-6-glucuronide (M6G) binds to opioid receptors to produce analgesic effects; however, data suggest that accumulation of this metabolite may also produce toxicity in patients with renal impairment.28, 45 This suggests that an alternative opioid should be used in patients with moderate to severe renal impairment. Oxycodone
Oral oxycodone has a high oral bioavailability (60%) and analgesic potency comparable to morphine.53As a single entity, it can be titrated
PHARMACOLOGIC MANAGEMENT OF PAIN
81
like morphine to effectively control severe pain.24It is available as a single entity 5-mg tablet, as a sustained release preparation (Oxycontin) dosed every 8 or 12 hours, and a liquid concentrate (20 mg/mL) for patients who have difficulty swallowing. Like morphine, the immediate release preparation should be dosed every 4 hours around the clock for continuous pain. There appears to be no appreciable accumulation of oxycodone's metabolites in patients with significant renal compromise. In this clinical situation oxycodone would be the preferred oral opioid to use. Hydromorphone Hydromorphone (Diluadid) can be administered by the oral, rectal, and parenteral routes. It has the same versatility as morphine. High oral dosing is limited by the tablet strengths currently available and necessity to take every 4 hours. A sustained release oral preparation is currently under development. It may be a useful substitute in patients who do not tolerate morphine because of side effects, especially when the parenteral route of administration is necessary. It is available in a high-concentration preparation (10 mg/mL) and has been shown to have a high bioavailability by continuous subcutaneous infusion (78%).43 Fentanyl Duragesic is a transdermal formulation of fentanyl that delivers 25, 50, 75, or 100 pg per hour as sustained-release opioid. When administered transdermally, the drug accumulates in the subcutaneous adipose which produces sustained concentrations of the drug in the bloodstream. The dosing interval for each system is every 72 hours, but interindividual variability exists, with some patients requiring a dosing interval of every 48 hours.52Indications for the transdermal route would include the unavailability of the oral route, poor compliance, or intolerable side effects associated with other opioids. Patients that are best suited for this delivery system are patients with fairly constant levels of pain.47In patients with rapidly escalating pain or patients at the end of life where the oral route is no longer available, parenteral administration of opioids would be preferred. Because of the delay in peak onset of analgesia after initial application (-20 hours), provisions for breakthrough doses of an immediate release opioid should be available by the oral, rectal, or parenteral route. Adjuvant Agents Adjuvant agents are drugs that are used to control side effects induced by analgesics (i.e., laxatives for constipation, antiemetics for nausea and vomiting) or have analgesic properties themselves. Drugs that have been identified as adjuvant analgesics are principally used to treat neuropathic pain. The applications of these agents in the palliative care setting are based on clinical studies in neuropathic pain states such a diabetic neuropathy or postherpetic neuralgia. Table 2 lists some common adjuvant analgesics
Table 2. ADJUVANT ANAGLESICS Drug
Starting Doses
Comments
Dexamethasone
1-2 mg orally twice a day
Amitriptyline
10-25 mg orally at bedtime
Gabapentin
100 mg orally three times a day
Metastatic bone pain, hepatic capsular distention: high dose (100 mg) for spinal cord compre~sion~~ Slowly titrate to analgesia--consider secondary arnines (desipramineor n~rtriptyline)~" if patient is bothered by anticholinergicside effects. Selective serotonin re-uptake inhibitors have poor efficacy for neuropathic pain42 Increase by 300 mg increments to analgesia, maximum dose of 3600 mg per day54
to consider for patients with pain refractory or only partially responsive to opioid therapy; detailed reviews on neuropathic pain are available.64, 65 Side Effects
Side effect management is an essential element of opioid therapy. Appropriate management of the following side effects can ensure that dose titration of the opioid can continue to doses high enough to produce effective analgesia. Constipation Constipation is the most common side effect seen with opioids and is a common occurrence in the palliative care setting.l6rZ3 Opioids induce constipation by decreasing intestinal motility and increasing anal sphincter tone, creating dried, hard stool that is difficult to evacuate. Survey data suggest that the transdermal fentanyl system (Duragesic) may cause less constipation than oral morphine.20Clinically, there appears to be no difference in the ability to cause constipationfrom one oral opioid to another one. The elderly are especially prone to constipation. It may be associated with abdominal pain and distention, nausea and vomiting, urinary retention, and cognitive impairment, leading to a decrease in the quality of life.8 Success in managing this side effect begins with understanding that tolerance to the constipating effects of opioids rarely develops. Constipation must be anticipated and treated prophylactically. Laxatives are to be titrated to the degree of constipation in the same way opioids are titrated to the severity of pain. The goal should be for comfortable defecation without a set frequency of bowel movements irrespective of prior bowel habits. Stool softeners are often ineffective alone in overcoming opioid effects on the bowel; a stimulant laxative (senna or bisacodyl) combined with oral hydration (if possible) is needed routinely. Osmotic laxatives (lactulose, sorbitol, or a magnesium containing product) can be added if needed. Constipation is a common reason for poor patient compliance with analgesic therapy. Patient and family education coupled with careful attention to bowel habits increases the chances for successful analgesic outcomes.
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Nausea and Vomiting Nausea and vomiting is commonly noted as an "allergy" in patient records. While not an allergy, nausea and vomiting is not as frequent a side effect as often believed, with an incidence estimated from 10% to 40%.9These effects are caused by opioid stimulation of the medullary chemoreceptor trigger zone (CTZ), increased vestibular sensitivity, and increased gastric antral tone. Tolerance to this effect develops quickly, so the prophylactic use of an antiemetic is not generally recommended. If this is a persistent problem, however, scheduled antiemetics may be helpful (e.g., Compazine 10 mg orally before meals and at bedtime) to allow tolerance to develop over the course of several days, after which a trial of withdrawing the antiemetic should occur. If nausea and vomiting persists, rotation to an alternative route (transdermal or parenteral) or alternative opioid would be indicated. Sedation Sedation is a common occurrence after initiation of o ~ i o i dtheravv or after dose escalation.In a patient who has had a long perioi of uncont;dled pain, exhaustion because of sleep deprivation is common. Long periods of sleeping after adequate analgesia has been achieved should not be considered caused by excessive opioid. The patient is catching up on much needed rest; pain is a powerful stimulus to keep us awake. If the patient is aroused easily, then the dose of opioid should not be reduced. Tolerance to sedation usually develops, but in some patients this may be a persistent side effect. Managing this problem begins with reviewing the medications that the patient is on and eliminating unnecessary central nervous system depressant medications. If pain relief is good, dose reduction can be attempted. If pain relief is unsatisfactory or pain reoccurs with dosage reduction, a psychostimulant can be added to the therapy. Methylphenidate (Rtalin) 5 to 10 mg at breakfast and lunch6with doses of up 20 mg twice daily may be used.'j4 Respiratory Depression Respiratory depression is a commonly feared side effect of opioid therapy. Respiratory depression rarely occurs when opioid doses are carefully titrated, and tolerance rapidly develops to this effect. Significant respiratory depression is seen with other central nervous systems effects including sedation and mental clouding. In the palliative care setting, especially with patients at the end of life, accumulation of opioid (or metabolites)may be the culprit. Withholding a scheduled dose or discontinuing regularly scheduled doses and continuing to have rescue doses available for breakthrough pain may be needed. If the patient is becoming progressively obtunded, cannot be awakened, or has severe respiratory depression, naloxone may be given in smallintravenous injections (0.4mg diluted in 10mL of saline, 1mL given every 1-2 minutes). The dose of naloxone should be sufficient to improve respiration (respiratoryrate > 10 or patient is aroused by
verbal stimuli) but without completely reversing analgesia, which causes severe pain and a withdrawal syndrome.39Naloxone has a short halflife; patients receiving sustained release morphine, sustained release oxycodone, transdermal fentanyl, or methadone may require repeated doses or a naloxone infusion to prevent recurrence of respiratory d e p r e ~ s i o n . ~ ~ Addiction versus Physical Dependence and Tolerance
There continues to be a popular myth that the use of opioids for pain control leads to addiction. This is in part because of confusion about the differences between addiction, physical dependence, and tolerance. Addiction is vsvcholoeic " devendence bn drum " with behavior centering on compulsive drug use (loss of control over drugs, prescriptions from multiple physicians, illegal means of procuring more drugs) and continued use, despite harm. This is a rare outcome of pain management, especially in a patient without a history of substance abuse. In a study of cancer patients who were treated with morphine for a total of 22,525 treatment days, only one patient developed problems related to substance abuse.66 Physical dependence is a process of neuroadaptation resulting from being exposed to exogenous opioids (similar to the effects seen with betablockers or alpha-2 agonists). This is generally seen in all patients taking re~ularlv " ,scheduled doses of ovioids after 7 to 10 davs. Abruvt discontinuation of the opioid may cause an abstinence syndrome characterized by tachycardia, hypertension, diaphoresis,piloerection, nausea and vomiting, diarrhea, body aches, abdominal pain, psychosis, and hallucinations. This by the administration of agonist-antagonist agents may be or by naloxone. This rarely is a clinical problem if patients are warned to avoid abrupt discontinuation and a tapering schedule in employed if opioid therapy is no longer necessary, such as after a neurolytic procedure. Patients currently abusing or with a history of substance abuse can also develop pain. Under-treatment of pain is an issue in these patients, especially AIDS patients, who tend to be younger and disproportionately comprised of substance abuser^.^ These patients deserve attentive treatment that may require consultation with a pain specialist to effectively manage their pain. Tolerance is the reduced effectiveness of a known dose of medication over time. Tolerance to opioid side effects is commonly seen (with the exception of constipation) and is desired. Tolerance to analgesia is rarely seen with continued use of opioids. Patients often have long periods where the dose of opioid needed for pain relief remains stable. Diminished pain relief from a previously effective dose is a clue to the clinician to suspect worsening of the underlying disease instead of tolerance to the opioid. I
-'
SUMMARY
Since the introduction of ether, a multitude of anesthesia and analgesia techniques have been introduced to ensure pain relief for our patients.
PHARMACOLOGIC MANAGEMENT OF PAIN
85
Several surgeons have made lasting contributions to the understanding and treatment of pain. Foremost in this area is Dr William K. Livingston, who chaired the Department of Surgery at the University of Oregon Medical School. In 1943, he published Pain Mechanisms outlining the specificity theory of pain. Pain and Sufeuing, published in 1998, 32 years after his death, describes his experimental and clinical observations as a researcher, clinician, and surgeon.37What is clear in Livingston's writings about his understanding and subsequent treatment of his patients is that everything is centered on the patient's report of pain. A surgeon fulfills his or her responsibility to effective pain management by using this central principle as the guidepost to the care of his or her patient. ACKNOWLEDGMENT The author wishes to acknowledge the assistance of Mary E. Campomizzi, PharmD, in preparing this article.
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Address reprint requests to James B. Ray, PharmD Department of Pharmacy and Drug Information Services Hamot Medical Center 201 State Street Erie, PA 16550