CHAPTER 30 Pain William S. Breitbart, Jessica Park mii . . , introduction . it «rhaps among the most prevalent and distressing symptoms FJ" Jtttd in Fatients Wlth ?ncer Ps>'chlatrlc psychological con in *e psycho-oncology setting must take into account the ■rt.nl relationships between pain and psychological and psychiatric ^ jin- Uncontrolled pain can mimic psychiatric disorders, so men Ihfilth clinicians must be knowledgeable about pain and its appropri-, laiipment to recognize cancer-related pain when it is present In %on,psychiatrists and psychologists can play a vital role in the mul-^ciPlinar>'aPProach lo managing cancer pain at all stages of disease. This chapter reviews the prevalence of pain in cancer, pain syndromes, mj pain assessment issues, as well as pharmacologic and nonpharma-gfcgk interventions for cancer-related pain. Psychiatric and psychoid interventions in the treatment of cancer pain have now become B integral pan of a comprehensive approach to pain management, and tee ire highlighted in this chapter. prevalence of pain Mn is a common problem for cancer patients, with approximately 70% of patients experiencing severe pain at some time in the course of their lass.1 It has been suggested that nearly 75% of patients with advanced cancers have pain,3 and that 50% of terminally ill patients are in moderate tosmrrepain.3 It is also estimated that 25% of enncer patients die in severe pain.1 There is considerable variability in the prevalence of pain among different types of cancer. For example, approximately 5% of leukemia paints experience pain during the course of their illness, compared to S0%-75% of patients with rumors of the lung, gastrointestinal (Gi) tract, or genitourinary system. Patients with cancers of the bone or cervix have wn found to have the highest prevalence of pain, with as many as 85% inpatients experiencing significant pain during the course of their illness.5 Dnp:te the high prevalence of pain, however, studies have shown that it u Huentjy underdiagnosed and inadequately treated," It is important t0 Member that pain is frequently only one of several symptoms that **w as part of a "cluster" of ph)-sical and psychological symptoms.6 With ™»se progression, the number of distressing physical and psychological ^nptorns increases so that patients with advance disease report an aver-v of II symptornSi A global evaluation of the symptom burden allows for ""otecomplex understanding of the impact of pain.7 lenso pain types and syndromes in cancer ional Association of Pain has defined pain as "an unpleasant ^ Interna^ . uisUerJa^em°tionaí experience associated with actual UStUe da "-AJJCUCI1CC BSSUCIUICU •»»•" — r , fain ha Tge W described in terms of such damage."* This definition or ^'"nal i!S?l.nne,Cted the concePt of Pain intensity being directly pro- liorai7Tnected the ^""P1 of Pain intensity being directly pra-"jectiv, ol)Jectivcly observable tissue damage, emphasizing the f'cr ^r("a'UrC °f the Pai" experience. In cancer pain patients how-WI (t5,icdly dramatic evidence of tissue damage that is etio-eis,cd to the pain complaint. This definition, particularly the Table3o-i. Classification of pa nociceptive pain ~ Sdlf?n^St,imU,-ti?n °f intact "no=i«P«ors" (pain receptors) includes omatic pain (involving skin, soft tissue, muscle, bone); n« j pai" (involvine internal organs, hollow viscera) responds to opioid and nonopioid analgesics Neuropathic pain Results from stimulation of damaged or compromised nerve tissue Kesporids to opioid and nonopioid analgesics AND adjuvant medications onset and termination characterizes acute pain. Generally, it is associated with subjective and objective physical or behavioral signs (e.g., grimacing, guarding, restlessness) and evidence of hyperactivity of the autonomic nervous system (e.g., rapid pulse, sweating). In contrast, chronic pain is pain that is experienced for longer than 3-6 months, or pain that persists beyond evidence of tissue damage healing. Patients with chronic pain often do not "look as if they are in pain" because adaptation of the autonomic nervous system occurs, and acute pain behaviors become replaced by depression, disability, and dysfunction. Chronic cancer pain can lead to significant changes in mood, personality, quality of life, relational problems, and functional ability' As such, this type of pain requires an approach that includes treatment of the cause of the pain as well as treatment of its psychological and social consequences* Pain can be further classified into two major categories based on pathophysiology: nociceptive and neuropathic pain (Table 30-1).10 Nociceptive pain derives from the stimulation of intact "nociceptors" or pain receptors in afferent nerves and is further subdivided into somatic pain (involving skin, soft tissue, muscle, and bone) and visceral pain (involving internal organs and hollow viscera). Nociceptive pain maybe well-localized (common in somatic pain) or more diffuse (common in visceral pain), and may be sharp, dull, aching, gnawing, throbbing, constant, or spasmodic, with varying intensity. Neuropathic pain involves stimulation of damaged or compromised nerve tissue, and may be burning, tingling, stabbing, shooting, with a sensation of electric shock, or allodynia (the sensation of pain or discomfort produced by a minimal stimulus such as light touch to the skin). The differentiation of pain into one of these subtypes (particularly nociceptive vs. neuropathic) can help in determining appropriate therapy, as discussed below. Foley" has categorized cancer pain syndromes based on temporal, etioS and contextual factors (Table 30-2) This approach to unde^ SSSg in«r pain syndromes provides clinicians with a useful classification when considering therapeutic approaches. multidimensional concept of pain MTn terminal illness ^oncnt 7 pain c°mpl«nt- This definition, panicum.? ľ'^rvoí , emPha»iKS Pain as an emotional experience as well - - nociceptive or physi- ? • Pa ľ/ demonstrates the need for psychosocial involve- ^ pai in «^"«Jg^ huIJ , S í ymťnI and management. , . „, " experience but involves complex uspc ^ ;í wä-*** ^ type on & ^ *tempo™. t**»* ^ «f nmy, ^ggs*« *• ^ ^do:y U>UW- P«n is often subtyped as acute pain or chronic net ,„ nole that the use * »«nporal characteristic*. A well-defined temporal pattern of It I» P Ml MANAf.rMi Ni or srrcinc symptoms 1. Patients wltl< ncule cancer-related I'"'" AasocUtcsl with the diagnosis of cancer Associated with ameer therapy (surgery, chemotherapy, <>r radiation) 2. Patients wIlli chronic cancer-related pnln Associated wllh enncer progression Associated wllh cmiccr iliernpy (surgery, chemothcropy. or radiation) , ■ , 3. Patient* Willi preexisting chronic pain nnd cnnccr-rclntcu pain •I. Patients with a history of drug addiction nnd canccr-rclntcu pain Actively involved in Illicit drug use In methadone maintenance programs With n history of drug use 5. Hying patients with cancer-related pnln found that women with mctastat.c breast cancer «p . pain If they believe the!r pain represents ,pread , Ly arc depressed. Belief about the mcantng of pal^c,nv „ mood disturbance were better pred.ctors of pain j^p^ site of metastases, Cancer pain and quality or life. In an attempt to dtfin ,1 3 In three *J«^.1*J^^^** psychologi. Somatic therapies -► Cognition Meaning of pain Emotion Suffering Socioenvlronment Social support Psychosocial therapies tint relationships between cancer pain and psychfj n«ll... Padil'la"ct i" found that there were &"-k\ka\u$? ablcs in three domains: physical well-being; psychol„KL°f1^,, (consisting of affective factors cognitive factors, ipirffi*^ municatlon skills, coping skills, and meaning attribute ln ccr); and interpersonal well-being (focusing on social 5UDn 'J'^ functioning). 'Ihc perception of marked impairment in C^''-daily living has been shown to be associated with increased ■ sity.17 Measures of emotional disturbance have been reported^ dlctors of pain in the late stages of cancer, and cancer paiiem.! Fig. 30-1. Ihc multidimensional nature of pain in cancer. always lead to pain relief and that the psychological factors play a modest but important role in pain intensity.13 'Ihc interaction of cognitive, emotional, socio-environmeutal, and nociceptive aspects of pain shown in Fig. 30-1 illustrates the multidimensional nature of pain in terminal illness and suggests a model for multimodal intervention.0The challenge of untangling and addressing both the physical and the psychological issues involved in pain is essential in developing rational and effective management strategies. Psychosocial therapies directed primarily at psychological variables have profound impacts on nociception, while somatic therapies have beneficial effects on the psychological aspects of nociceptive pain. Ideally, such somatic and psychosocial therapies arc used simultaneously in a multidisciplinary approach to pain management In the cancer patient." PSYCHOLOGICAL FACTORS IN THE CANCER PAIN EXPERIENCE Among the many stressors faced by patients with cancer are dependency disability, and fear of painful death. Such fears are universal; however the level of psychological distress is variable and depends on medical factors, social support, coping capacities, nnd personality. Cancer pain and distress. Cancer-relntcd pain has profound effects on psychology distress; and psychological factors such ITanxictv Set Sr.™*en?; ta w fr tricm pane,,,! who est. r; ^: &rwtd ** can«r less interference will, their actlvvIn I, n,r ™T C*UM rePort ccr); and interpersonal well-being (focusing on social SUDP.a,nr'; functioning). 'Ihc perception of marked impairment in w t; • daily living has been shown to be associated with increased " ; itO - Patient-v1'. anxiety nnd depression are less likely to report pain." in a ' study of cancer patients, it was found that maladaptive coping gles, lower levels of self-efficacy, and distress specific to treaty!* disease progression were modest but significant predictors of pain intcnsity.u c Psychological variables, such as the amount of control peopkbeP they have over pain, emotional associations and memories of pai^ of death, depression, anxiety, and hopelessness, contribute to theanr-ence of pain and can increase suffering. Singer and colleagues^ ttp^j an association among the frequency of multiple pains, incrcisei di ability, and higher levels of depression. All too frequently, psychoid variables ore proposed to explain continued pain or lack of respenek therapy \s*hen in fact medical factors have not been adequately appsc-atcd. Often, the psychiatrist is the last physician to consult on a case paticnt with pain. In that role, one must be vigilant that an accurals ft; diagnosis is made and must be able to assess the adequacy of thte.ti cal analgesic management provided. Personality factors may be cm distorted by the presence of pain, and relief of pain often results act disappearance of a perceived psychiatric disorder.10 CANCER PAIN AND PSYCHIATRIC DISORDERS there is an increased frequency of psychiatric disorders in cartf patients with pain. In the Psychosocial Collaborative Oncology Gr^ Study31 on the prevalence of psychiatric disorders in cancer p* 39% of the patients who received a psychiatric diagnosis (Table reported significant pain, whereas only 19% of patients wthoat ipT chiatric diagnosis had significant pain. The psychiatric dlS1^'^ cancer patients with pain primarily included adjustment diso. ^ depressed or anxious mood (69%) and major depression (b ^ finding of increased frequency of psychiatric disturbance m pain patients also has been reported by other investigators. . dencc and patterns of psychiatric disorders may vary system £ ^ subgroups of patients. For example, Steifel et al.a descn^rn.entfr-' chiatric complications seen in cancer patients undergoing1 epidural spinal cord compression (ESCC), which may rncw"akf dexamcthasonc (as much as 96 mg/day for up to a week, tapering course for up to 3 or 4 weeks). Twenty-two per" ^a*1' with ncrr u.j___:___i______:________1_____Jiaunosed as ' with ESCC had a major depressive syndrome diagnoses^ 4% in the comparison group. Also, delirium was muc ^ ^ in the dexamethasone-treated patients with ESCC, toor with delirium during the course of treatment as cOfflP" in the comparison group Although there is llmi other subpopulations, it is apparent that advan cancer ?^ w • iron1 psychiatric consultation has been found to ranS . 0f and to he ns high us 85% during the terminal staS"-1- organic mental disorders (delirium) among ^ -,H,f> PAIN 217 bfeJO-* RateS of DSM"UI Ps>'dliatric disorders and prevalence of pain observed in 215 cancer patients from three cancer center* Number in diagnostic class ,nt disorders Arrive disorders Mental disorders .-disorder* Percentage of psychiatric diagnoses ^ri5ä"i«tricdiToiis. To^!ľ L psychiatric diagnosis 69 13 8 7 4 101 114 215 ■ 32 6 4 3 2 47 53 100 Number with significant pain" 68 13 8 4 39 (39%) 21 (19%) 60 (28%) ,hin 50 mm on a 100 mm VAS pain severity. '^mTios: VAS, visual analogue scale till*- j fjjes and many other drugs can cause confusional states, particu-jSfo the elderly and terminally ill * CANCER PAIN AND SUICIDE Uncontrolled pain is a major factor in suicide and suicidal ideation in oncer patients.1* The majority of suicides observed among patients wish oncer had severe pain, which was often inadequately controlled or tolerated pooriy.;; Although relatively few cancer patients commit suicide, they are at increased risk. Pain is both a unique and synergistic contributor to suicide risk in cancer patients. For more details on suicide and desire for hastened death in cancer patients, please refer to Chapter 43. CANCER PAIN ASSESSMENT Ik initial step in cancer pain management is a comprehensive assessment of pain symptoms. An important element in assessment of pain is the concept that assessment is continuous and needs to be repeated over recourse of pain treatment. There are essentially four aspects of pain eiperience in cancer that require ongoing evaluation, and they include pan intensity, pain relief, pain-related functional interference (e.g., mood state, general and specific activities), and monitoring of intervention effects (e.g., analgesic drug side effects, abuse).5" Table 30-4 outlines the principles of pain assessment as described by holey.1 The Memorial ^Assessment Card (MPAC)M is also a helpful clinical tool that allows Patients to report their pain experience. The M PAC consists of visual ■alog scales that measure pain intensity, pain relief, and mood. Patients c«i complete the MPAC in less than 30 seconds. Patients' reports of pain •niensuy, pain relief, and present mood state provide the essential infor-*«ion required to help guide their pain management. The Brief Pain toftntory" is another pain assessment tool that has useful clinical and "arch applications. Table 30-4. Principles of pain assessment Btlievo ik . Patl«nts complaint of pain 3.^bailed history i. Psychosocial status of the patient 5-Ord 3 Mreful medical and neurological examination procedu Pcrsonally review the appropriate diagnostic '■Tfeit tlf**. patiem's extent of pain '■CoiJj, P?m to facilitate the diagnostic work-up filial , e aller»ative methods of pain control during V Ktau lua,'on the initial . ,lel • IW.*Va!u«ion mplaint during the prescribed therapy ■ INADEQUATE CANCER PAIN MANAGEMENT Inadequate management of cancer pain is often a result of the inability to properly assess pain in all its dimensions." All too frequently, psychological variables are proposed to explain continued pain or lack of response to therapy, when in fact medical factors have not been adequately appreciated. Other causes of inadequate pain management include lack of knowledge of current pharmacotherapeutic or psychotherapeutic approaches; focus on prolonging life rather than alleviating suffering; lack of communication between doctor and patient; limited expectations of patients regarding pain relief; limited communication capacity in patients impaired by organic mental disorders; unavailability of opioids; doctors' fear of causing respiratory depression; and, most important, doctors' fear of amplifying addiction and substance abuse. In cancer, several additional factors have been noted to predict the under-management of pain, including a discrepancy between physician and patient in judging the severity of pain; the presence of pain that physicians do not attribute to cancer; better performance status; age of 70 years or more; and female sex.31 Fear of addiction and Inadequate cancer pain management. Fear of addiction affects both patient compliance and physician management of narcotic analgesics, leading to undermedication of pain in cancer patients." Studies of the patterns of chronic narcotic analgesic use in patients with cancer have demonstrated that, although tolerance and physical dependence commonly occur, addiction (psychological dependence) is rare and almost never occurs in individuals without a history of drug abuse before cancer illness." Studies of the patterns of chronic narcotic analgesic use in patients with cancer have demonstrated that, although tolerance and physical dependence commonly occur, addiction (psychological dependence) is rare and almost never occurs in individuals without a history of drug abuse before cancer illness" reported on their experience in managing cancer pain in such a population. Of 468 inpatient cancer-pain consultations, only eight patients (1.7%) had a history of intravenous (IV) drug abuse, but none had been actively abusing drugs in the previous year. All eight of these patients had inadequate pain control, and more than half were intentionally undermedicated because of staff concern that drug abuse was active or would recur. Adequate pain control was ultimately achieved in these patients by using appropriate analgesic dosages and intensive staff education. Concerns over respiratory depression and inadequate cancer pain management. The risk of inducing respiratory depression is too often overestimated and can limit appropriate use of narcotic analgesics for pain and symptom control. Bruera et al.41 demonstrated that, in a population of terminally ill cancer patients with respiratory failure and dyspnea, the administration of subcutaneous morphine actually improved dyspnea without causing a significant deterioration in respiratory function. management of specific symptoms 216 L,ck of concordance between patient and caregiver assessment „f r,„ln Intensity The adequacy of cancer pain management can be SffJdTS?lack of concordance between patient ratings or com-^thli p in and those made by caregivers. Persistent cancer n l:oln ascribed to n psychological cause when it to treatment attempts. In our clinical exper.ence, we base noted ma p.S who report their pain as severe are quite likely to be viewed-E ng a psychological contribution to their complaints Sjrfmemberf ability-to empathize with a patients pain complaint may be limited by the intensity of the pain complaint. Grossman et al.» found that. while there is a hich decree of concordance between patient and caregiver ratings ol patient pain intensity at the low and moderate levels, this concordance breaks down at high levels. Thus, a clinicians ability to assess a patients level of pain becomes unreliable once a patient's report of pain intensity rises above 7 on a visual analogue rating scale of 0-10. Physicians must be educated as to the limitations of their ability to objectively assess the severity of a subjective pain experience. In addition, patient education is often a useful intervention in such cases. PSYCHIATRIC MANAGEMENT OF PAIN IN CANCER Optimal treatment of pain associated with cancer may require a multimodal strategy, including pharmacological, psychotherapeutic, rehabilitative, and interventional approaches. Psychiatric participation in pain management involves the use of psychotherapeutic! cognitive-behavioral, and psychopharmacologic interventions, usually in combination. PSYCHOTHERAPY AND CANCER PAIN The goals of psychotherapy with cancer patients with pain arc to provide support, knowledge, and skills (Table 30-5). Utilizing short-term supportive psychotherapy focused on the crisis created by the medical illness, the therapist provides emotional support, continuity, information, and assists in adaptation. The therapist has a role in emphasizing past strengths, supporting previously successful coping strategies, and teaching new coping skills, such as relaxation, cognitive coping, use of analgesics, self-observation, documentation, assertiveness, and communication skills. Communication skills are of paramount importance for both patient and family, particularly around pain and analgesic issues. The patient and family are the unit of concern, and need a more general, long-term, supportive relationship within the healthcare system in addition to specific psychological approaches dealing with pain and dying which a psychiatrist, psychologist, social worker, chaplain, or nurse can provide. Utilizing psychotherapy to diminish symptoms of anxiety and depression, factors that can intensify pain, empirically has beneficial effecte on cancer pain experience. Spiegel and Bloom* demonstrated, in a controlled randonuzed prospective study, the effect of hoth supportive groupTer apy for metastatic breast cancer patients in general and, in paniculaThe effect ofhypnotic pain control exercises Their sunnnn llr, pa"™'tnc _ Wtn advanced disease Goals Form Support—provide continuity Knowledge—provide information Skills—relaxation cognitive coping use of analgesics communication Individuals—supportive/crisis intervention Family—patient and family the unit of concern Group—share experiences identify successful co strategies are aping 'Ihe treatment patients experienced significantly less pair, th,n patients. Those in thc group that combined a self-hypnosis eXerc' C°r',r showed a slight increase, and thc control group showed a lar^^'v in pain. lriCTtiv Group interventions for individuals with cancer pain (even ;n stages of disease) arc a powerful means of sharing experience l^i tifying successful coping strategics. Thc limitations of usim; t>r' eain'iT C°ndi!ioninE- Pai" behavior is reinforced and continues Pam behaviors resulting from rest) d l cntl0n and caring experiences can elicit increasedK« °r cnndi''°ni»E- Stimuli associated with prior painful Redefinition of some or all aspect f h avoidance behavior resulting in decreased distress0 ILE? '"terPretation of the noxious or threatening experience. Written or audiotaped chronide thTlv, hopclessness ^ associated with pain Patient maintains to describe specific agreed-upon characteristics by theBpaftfcnteMe^ responses that either reinforce or inhibit specific behaviors exhibited A hierarchy of tasks i e phvsi 7 rcmforcinB d«^d "well" behaviors mental imagery, ^S^^^^^^^^^ pain 219 ttchniques and behavioral techniques. Both techniques comprise a range of techniques including passive relaxation with mental imager)', cognitive distraction or focusing, progressive muscle relaxation, biofeedback, hypnosis, and music therapy.^ The goal of treatment is to guide the patient toward a sense of control over pain. Some techniques are primarily cognitive in nature, focusing on perceptual and thought processes, and others air directed at modifying patterns of behavior that help cancer patients cope with pain. Behavioral techniques for pain control seek to modify physiologic pain reactions, respondent pain behaviors, and operant pain behaviors (see Table 30-7 for definitions). Relaxation techniques. Several techniques can be used to achieve a mental and physical state of relaxation. Muscular tension, autonomic arousal, and mental distress exacerbate pain.'104' Some specific relaxation techniques include (1) passive relaxation focusing attention on sensations of warmth and decreased tension in various pans of the body, (2) progressive muscle relaxation involving active tensing and relaxing of muscles, and (3) meditation. Hypnosis. Hypnosis can be a useful adjunct in the management of oncer pain*3"1-* Hypnotherapy, usually involving the teaching of seli-bypnotic techniques, can be used effectively in the management ot pain »»ociated with invasive procedures.46 In a controlled trial comparing "If hypnosis with cognitive-behavioral therapy in relieving mucositis following a bone marrow transplant, patients utilizing "Ported a significant reduction in pain compared to patients who used «>Enilive-behavioral techniques." The hypnotic trance is essentia y a j* of heighten* d and focused concentration, and thus it can be useci 10 manipulate the perception of pain. ^encephalography (eeg) biofeedback-assisted re 1«^2lA H«p were able to maintain analgesia after the 7 of generalization of effect can be a problem with biofeedback tec 55" A1*ough physical condition may make a pnJ^jSJ «ten use EMG and temperature bio taxation-assisted pain control.4" pain management protocol. The partner-guided pain management training protocol was a three-session intervention conducted in patients' homes that integrated educational information about cancer pain with systematic training of patients and partners in cognitive and behavioral pain coping skills. Data analyses revealed that the partner-guided pain management protocol produced significant increases in partners' ratings of their self-efficacy for helping the patient control pain and self-efficacy for controlling other symptoms. AROMATHERAPY Aromas have been shown to have innate relaxing and stimulating qualities. Our colleagues at Memorial Hospital have recently begun to explore the use of aroma therapy for the treatment of procedure-related anxiety (i.e., anxiety related to magnetic resonance imaging [MR1J scans). Utilizing the scent beliotropin, Manne et al.50 reported that two-thirds of the patients in their study found the scent especially pleasant and reported feeling much less anxiety than those who were not exposed to the scent during MRI. As a general relaxation technique, aroma therapy may have an application for pain management, but this is as yet unstudied. PHARMACOTHERAPIES FOR PAIN Although the management of analgesic medications is more often undertaken by the oncologist or palliative care specialist, it is essential that the psycho-nncolngist have a thorough understanding of the analgesic medications most often used in the management of cancer-related pain. The World Health Organization (WHO) has devised guidelines for analgesic management of cancer pain that the Agency for Health Care Policy and Research (AHCPR) has endorsed for the management of pain related to cancer.'1 These guidelines, also known widely as the WHO Analgesic Ladder (see Fig. 30-2), have been well validated." This approach advocates selection of analgesics on the basis of severity of pain. For mild to moderately severe nain nonopioid analgesics such as nonsteroidal antiinflammatory drugs (NSAIDs) and acetaminophen are recommended. For pain .feedback'techniques for learn- ° b pcrsistcnt and moderatc to severe in intensity, opioid anal-1 1" L It i-^-Jno notencv (such as morphine) should be used. JS 1 Wwsodal Interventions. It *^*£^jSi t rT P^osocial interventions for cancer pain example, Keefe et al.4' tested the efficacy of a partner-guided «sics of increasing potency (such as morphine; should r>e usee Adjuvant agents, such as laxatives and psychostimulants, arc useful fn n eventiSg as welt as treating opioid side effects such as constipa-Smor sedation, respectively. Adjuvant analges.c drugs, such as the 220 MANAGEMENT OF SPECIFIC SYMPTOMS Freedom from cancer pain Opioid for moderate to severe pain ± Nonoplokl ± Adjuvant Pain persisting or Increasing Opioids for mild to moderate pain ± Nonopioid ± Adjuvant Pain persisting or Increasing Nonopiold ± Adjuvant Pain Fig. 30-2. WHO Analgesic Ladder. source: Adapted from Cancer pain relief, with a guide to opioid availability. 2nd ed. Genera; World Health Organization; 1996. antidepressant analgesics, are suggested for considered use, along with opioids and NSAIDs, in all stages of the analgesic ladder (mild, moderate, or severe pain). Portenoy" have described the indications for and the use of three classes of analgesic drugs that have applications in the management of cancer and acquired immunodeficiency syndrome (AIDS) patients with pain: nonopioid analgesics (such as acetaminophen, aspirin, and other NSAIDs), opioid analgesics (of which morphine is the standard), and adjuvant analgesics (such as antidepressants and anticonvulsants). NONOPIOD ANALGESICS (NSAIDs) The nonopioid analgesics (Table 30-8) are prescribed principally for mild to moderate pain or to augment the analgesic effects of opioid analgesics in the treatment of severe pain. The analgesic effects of the NSAIDs result from their inhibition of cyclooxygenase and the subsequent reduction of prostaglandins in the tissues, The concurrent use of NSAIDs or acetaminophen and opioids provides more analgesia than does either of the drug classes alone. In contrast to opioids, NSAIDs have a ceiling effect for analgesia, do not produce tolerance or dependence, have antipyretic effects, and have a different spectrum , 1 effects. lhc NSAIDs' mechanisms of action, phnrjnacnkjn, mncodynamics influence (lie analgesic response, 'H,/ ,C1, aN NSAID should lake itito account the etiology an(| .,v„?'*c,lrin ■ - j!—1............U.i----l. , cr"y (iflhf''r, f' 'lr-, cri.. NSAID should be titrated to effect as well as to side CfTccts variability in patient response to both relief and adverse rea "iv results arc not favorable, nn alternative NSAID should be triej ;if^ MAJOR ADVERSE EFFECTS OF NSAIDs The major adverse effects associated with NSAIDs include concurrent medical conditions that may be relative com :"ntN (e.g., bleeding diathesis), associated symptoms, and fivorihl ^ by the patient as well as the physician. From a practical nJ CtxN,.' ation, renal failure, hepatic dysfunction, and bleeding. Theujj!§t ^ has been associated with a variety of GI toxicities, including mj lD> pepsia and heartburn, as well as major gastric erosion, pCptjc uicw^ tion, and GI hemorrhage. The nonacctylatcd salicylates, such ^7 sodium salicylate, and choline magnesium salicylate, theoretical! ^ fewer GI side effects and might be considered in cases where G] 1 is nn issue. Prophylaxis for NSAlD-associatcd GI symptoms J''?1 H2-antagonist drugs (Cimetidine 300 mg tid-qid or ranitidine 150 mjV? misoprostal 200 mg qid; omeprazole 20 mg qd; or an antacid, toi .' should be informed of these symptoms, issued guaiac cards with reu^ and taught to check their stool weekly. NSAIDs affect kidney function should be used with caution. Prostaglandins are involved in the autort-^ lation of renal blood flow, glomerular filtration, and the tubular trjjJ£ of water and ions. NSAIDs can cause a decrease in glomerular filtratioa acute and chronic renal failure, interstitial nephritis, papillär)' necnx\ and hyperkalemia." In patients with renal impairment, NSAIDs shouldbc used with caution, since many (i.e., ketoprofen, feroprofen, naproxen, uj carpofen) arc highly dependent on renal function for clearance, Ihe rd of renal dysfunction is greatest in patients with advanced age, preabtb renal impairment, hypovolemia, concomitant therapy with nephrctorc drugs, and heart failure. Prostaglandins modulate vascular tone, and their inhibition by the NSAIDs can cause hypertension as well as interference with the pharmacologic control of hypertension." Caution should be used in patients receiving ß-adrenergic antagonists, diuretics, or angiotensin-converting enzyme inhibitors. Several studies have suggested that there is substantial biliar)1 excretion of several NSAIDs, including indomethii and sulindac. In patients with hepatic dysfunction, these drugs shcü be used with caution. NSAIDs, with the exception of the nonacttylu«! salicylates (e.g., sodium salicylate, choline magnesium trisaliq-late], produce inhibition of platelet aggregation (usually reversible, but irrevcreb!; with aspirin). NSAIDs should be used with extreme caution or avoided in patients who are thrombocytopenic or who have clotting impairment Table 30-8. Oral analgesics for mild to moderate pain in cancer Starting dose Plasma Analgesic (by class) (mg) duration (hrs) (hrs) Nonsteroidal Aspirin 650 4-6 4-6 Ibuprofen Choline magnesium t ri salicylate 400-600 700-1500 — Weaker opioids Codeine 32-65 3-4 Oxycodone 5-10 3-4 Proxyphenc 65-13 4-6 Comments The standard for comparison among nonopioid analgesics Like aspirin, can inhibit platelet function Essentially no hematologic or gastrointestinal s effects Metabolized to morphine, often used to sujtf-cough in patients at risk of pulmonary W ^ Available as a single agent and in combine aspirin or acetaminophen jin Toxic metabolite norpropoxy accumulate repeated usage AfNSAlDs In patients with cancer and AIDS must h, Ihf "'id bv heightened awareness o toxicity and adverse efccU highly protein hound, and the free fraction of ava . £>s " incren.«d in cancer patients who are cachectic, wasted i"ir,lh..minic- odcu resulting in toxicity and adverse efTects SW^Si «,,CCr ^req"Cn,ly hyP°wlemlc and on concur Un'\atoxic drugs and so are at increased risk for renal toxic S>< n' detCCti°n °f infcCtion !" Patients "ccd ror alteration. ■ PAIH Info, 1ht of ana «£ l T'^ *ldi « f«<"« or IV „f?lt P'0ld'S in,titu*<3. E!'1^0rt" continuous S»! .A) devices- has become Pa«'«nt-control!ed anal- Jtlentl with escalating pri„ .„TlnTm-Mp,"M h c"1* for "n«r lat= stages of discasc Pmn and in hosp.ee and home settings during ff -nterfc« ,%'ltn J ™«™ »■ "»«.xiran in patients with u, ,t,'ls w»h escalating pain and inrpia" ,n carinS for c^«r 0 ,nK latc staG« of disease In h°SP'« and home settings during c*"c( v ? inhibitors have an analgesic action equal to that of conven <:?vN\IDs, but with fewer GI complications and have been widely "tes of administration Th. „ , cumatic diseases* COX-2 inhibitors are associated wTth an r°U,e °f adminis'ration ofolioul£ !"5 ! ° ,hc prcferred <*i **£ of adverse cardiovascular events, including 'forSo? T'6™"« and c<^ taXÄ6"" £ pcT?iw °f s:n ulceration, bleeding and perforation, and are contraindicatcd n110"'____tmpnt of perioperative pain in the settinr of mm------ ^ ulceration, bleeding and perloration, and are contraindicatcd fZ treatment of perioperative pain in the setting of coronary artery opioid analgesics Opioid analgesics are the mainstay of pharmacotherapy of moderate to ft intensity pain in the patient with cancer (see Table 30-9). ]n choosing the appropriate opioid analgesic for cancer pain, Portcnoy57 severe |HUH'"---D i ■ ■ " --------r----t'vivuu; highlights the following important considerations: opioid class, choice of •weak" versus "strong" opioids, pharmacokinetic characteristics, duration of analgesic effect, favorable prior response, and opioid side effects (Table 30-10). Opioid classes. Opioid analgesics are divided into two classes: the aeoniits and the agonist-antagonists, on the basis of their affinity to opioid receptors, Pentazocine, butorphanol, and nalbuphine are examples of opioid analgesics with mixed agonist-antagonist properties. These drugs can reverse opioid effects and precipitate an opioid withdrawal syndrome in patients who are opioid tolerant or dependent. They are of limited use in the management of chronic pain in cancer and AIDS. Oxycodone (in combination with either aspirin or acetaminophen), hydrocodone, and codeine are the so-called weaker opioid analgesics and arc indicated for use in step 2 of the WHO ladder for mild to moderate pain. More severe pain is best managed with morphine or another of the "stronger" opioid ^algesics, such as hydromorphone, methadone, levorphanol, or fenta-nyl. Oxycodone, as a single agent without aspirin or acetaminophen, is available in immediate and sustained-release forms and is considered a longer opioid in these forms. Oxymorphone, including Numorphan, fyana, and Opana ER, is a potent opioid analgesic. They act quickly *n taken orally and have significantly longer half-lives than mor-Phine. Rectal administration is an alternative for those patients unawe ,0 take oral medications. Equianalgesic dosages may be due to pharmacokinetic differences. . Pharmacokinetics. A basic understanding of »Jie ph^coto^a of analgesics- is important for the cancer and AIDS «*gwM* ^analgesics with long half-lives, such as «««^^$ndr fer? proximately 5 days to achieve a steady ^"Jgrf* ives, the duration of analgesia that they V^^cry 4-6 c) a Lm°st patients rec*uire admin,stra 3 to accumulate with 3£i?,,ho* methadone and levorphanol tend Seda- Wa„d dosine-dela^ of «oridtycan de P ' '"ore rarely, respiratory depression). ■ifi.0" "fleets. The duration of w^^SATrf jrs of re ..clock *^*%?^^l™^nf «PioÄ aSite £ ^VTOUed bV rcE- irtn^ nl^" «;needcd basis to determine the patient's total daily k<1u minimise toxicity (due to its long half-life). .„ Op,old rotation is a useful strategy to improve p»» & «P««al y m long-term treatment. Accumulation *f f ^ «n lead to the development of symptoms that lndu* Tj,b[c3o-*o. Principles of opioid analgcsic U; lowest dose posMble l í'tratf á%cd" doses selectively i tV*1' "propriatc route of administration j mfln "f J,f equivalent analgesic doses j. Ff '^Lbination of opioid, nonopioid, and adjuvant d * L of tolerance ?,LTnder*tand physical and psychological dependence j^nus nausea and vomiting, and persisting pain Sev*roi . ^rotation using equianalgesic doses h" been1 '" 223 Irugs I --""'vgics Slin" managing pain while decreasing the toicSe^^ nev and severity of opioid toxicity,60 wel1 w th= si(le effects. While the opioids are extremely effective analgesics y 5ide effects are common and can be minimized if anadpateddn Sw«.Sedation is a common central nervous system (CNS) side effect iptcUll) 'during the initiation of treatment. Sedation usually resolves i the patient has been maintained on a steady dosage. Persisten stdation can be alleviated With a psychostimulant, such as dextroam phetamine, pemoline, or methylphenidate. All are prescribed in divided doses in early morning and at noon. In addition, psychostimulants can improve depressed mood and enhance analgesia.61 Delirium, of either an agitated or a somnolent variety, can also occur while the patient is cn opioid analgesics and is usually accompanied by attcntional deficits, disorientation, and perceptual disturbances (visual hallucinations and! more commonly, illusions). Myoclonus and asterixis are often early signs of neurotoxicity that accompany the course of opioid-induced delirium. Meperidine (Demerol), when administered chronically in patients with renal impairment, can lead to a delirium resulting from accumulation of the neuroexcitatory metabolite normcperidine." Opioid-induced delirium can be alleviated through the implementation of three possible strategies: lowering the dose of the opioid drug presently in use, changing to a different opioid, or treating the delirium with low doses of high-potency neuroleptics, such as haloperidol. 'Ihe third strategy is especially useful for agitation and clears the sensorium." For agitated states, IV haloperidol in doses starting at between 1 and 2 mg is useful, with rapid escalation of dose if no effect is noted. Gastrointestinal side effects of opioid analgesics are common. The most prevalent are nausea, vomiting, and constipation/4 Concomitant therapy with prochlorperazine for nausea is sometimes effective. Since all opioid analgesics are not tolerated in the same manner, switching to another narcotic can be helpful if an antiemetic regimen fails to control nausea. Constipation caused by narcotic effects on gut receptors is a problem frequendy encountered, and it tends to be responsive to the regular use of senna derivatives. A careful review of medications is imperative, since anticholinergic drugs todi as the tricyclic antidepressants (TCAs) can worsen opioid-inaucea ^nstipaii0n and can cause bowel obstruction. Respiratory depression »»worrisome but rare side effect of the opioid analgesics. R«p£rtory acuities can almost always be avoided if two general pnnapte are •tiered to: start opioid analgesics in low doses ™°?10*™™J^ «* be cognizant of relative potencies when switching opioid analgesics, ro"les of administration, or both psychotropic adjuvant analgesics ^Patient with advanced disease and pain has «^£^X£ froPriate and maximal utilize in the J* Particularly the TCAs, are useful as ad,u,w>, «£ges geological management of cancer pain ^ ^h anal^sic Z, 30-U ,ists the various P^otrop.c medKah address ng a wide variety of chronic pains/7 Other TCAs that have been shown to have efficacy as analgesics include imipramine,* desipramine, nortriprvlineclomipramine,71 doxepin,71 and sertraline.7' In a placeoo-controlled double-blind study of imipramine in chronic cancer pain, Walsh7' demonstrated that imipramine had analgesic effects independent of its mood effects, and was a potent co-analgesic when used along with morphine. Sertraline has been showed to reduce hot flashes in early stage breast cancer patients taking tamoxifen; however, compared to a placebo the reduction was not significant.75 In general, the TCAs arc used in cancer pain as adjuvant analgesics, potentiating the effects of opioid analgesics, and are rarely used as the primary analgesic,76 Ventafridda et aL* reviewed a multicenter clinical experience with antidepressant agents (trazodone and amitriptyline) in the treatment of chronic cancer pain that included a deafferentation of neuropathic component. Almost all of these patients were already receiving weak or strong opioids and experienced improved pain control. A subsequent randomized double-blind study showed both amitriptyline and trazodone to have similar therapeutic analgesic efficacy.7* Magni et al.77 reviewed the use of antidepressants in Italian cancer centers and found that a wide range of antidepressants were used for a variety of cancer pain syndromes, with amitriptyline being the most commonly prescribed, for a variety of cancer pains. In nearly all cases, antidepressants were used in association with opioids. There is some evidence that there may be a subgroup of patients who respond differentially to tricyclics and therefore if amitriptyline fails to alleviate pain, another tricyclic should be tried, The TCAs are effective as adjuvants in cancer pain through a number of mechanisms that include (1) antidepressant activity, (2) potentiation or enhancement of opioid analgesia,71 and (3) direct analgesic effects.7' The heterocyclic and noncydic antidepressant drugs such as trazodone, mianserin, maprotiline, and the newer SSRIs, fluoxetine and paroxetine may also be useful as adjuvant analgesics for cancer pat'icnts with pain however, clinical trials of their efficacy as analgesics have been equivocal. There are several case reports that suggest that may be a useful adjuvant analgesic in the management o?headach - Although i, has not been toJon^^gS? u' ^ has also been shown to heln with P L.' Such M <= talopram newerSSRJ, ,1as J££^Q^it^^^ t>v.ty in its class, no active metabolite ^ the selec- the CYP450 isoenzyme." While E t'Z sign*'antly affect cancer pair, j has been JJ*pram has not been tested ^ SSRIs may offer greater benefit to S dePressi°n and anxiety." improvemenu in quality. o«^£2^ as fenced by're at as SiTvSCf 2 Newer antid clinically „ fu[[™ "e> "redone, and SZ££%P**m such as adjuvant analgesics. NefaSg? f^° 3pPear <° be ' f0r mst»nce, has "íľnaÄnsity following treat- t breast ^ nstrecently^ithduloxetine t . Small sample mirtazapine has been shown to impr AuTicallv significant, pain, nausea, appetite, insomJ-^S 2 Gat we small, bu, one must consider that patients j^i^ S'SSJ to show decline in these symptoms, not irnpr^ F«ynhagen et al« has shown that .n a large sample ofgjjg r Thnselinc to endpoint (a 6-weck period), mirtazapine siJmS [mprovestTin. sleep disturbances, irritability, and exhaustiorTS Appropriate dosage of antidepressant adjuvant anal^t, . terms of appropriate dosage, there is evidence that the theraw analgesic effects of amitriptyline are correlated with serum lcv£ the antidepressant effects are, and analgesic treatment failure Ua low serum levels." A high-dose regimen of up to 150 mgofamfcT tvllnc or higher is suggested.'4 As to the time course of onset of cesia or with antidepressants, there appears to be a biphasic proco, that occurs with immediate or early analgesic effects that occur wife hours or days71 and later, longer analgesic effects that peak over »4-to 6-week period.*7 Treatment should be initiated with a small dose of amitriptyline; for instance, that is, 10-25 mg at bedtime especially in debilitated partes* and increased slowly by 10-25 mg every 2-4 days toward 150 mg wti, frequent assessment of pain and side effects until a beneficial effect ď achieved. Maximal effect as an adjuvant analgesic may require confc-ation of drug for 2-6 weeks. Serum levels of antidepressant drug, when available, may also help in management to assure that therapeutic terce levels of drug are being achieved. Both pain and depression in cancer patients often respond to lovn doses (25-100 mg) of antidepressant than are usually required in the physically healthy (100-300 mg), most probably because of impiLti metabolism of these drugs. Choosing the appropriate antidepressant ad|uvant analges* drug. The choice of drug often depends on the side-effect profile, existing medical problems, the nature of depressive symptoms if present, M past response to specific antidepressants. Sedating drugs like amitnp tyline are helpful when insomnia complicates the presence of depression on a cancer patient. Anticholinergic properties of some^ these drugs should also be kept in mind. Occasionally, in p*j«* have limited analgesic response to a tricyclic, potentiation of i^i can be accomplished with the addition of lithium augmentation. Tricyclic antidepressants have been shown to be as effective as sics for mucositis when compared to opioids and for patients tor opioids are contralndicated TCAs may be used.96 MONOAMINE OXIDASE INHIBITORS ^ Monoamine oxidase inhibitors (MAOIs) are less useful in ^Jjjjrf ting because of dietary restriction and potentially dangerous u« ^ between MAOIs and narcotics such as meperidine. Amongst n , drugs available, phenelzine has been shown to have adjuva"' Properties in patients with atypical facial pain and mign»ne' ANTICONVULSANTS ^jd S™TJ a"tic«"vulSant drugs appear to be analgesic ri;„; i as *nat characterize dive rse tyre* oi nc«» .„ ^ w h rt ^"'"^ ^ ouS dysesthesias; Although, in the past, practitioners ^ l^n.^pine because of he good response rates observed £ P t%\#*W* lib. generally, not currently perceived as a fij" analpes.c. Carbamazepine must be used caution! with thrombocytopenia, those at risk for marrow failure in £ whose blood counts must be monitored to determine disease »"Jt < veral newer anticonvulsants are now commonly used in thl nf neuropathic pair,..particularlyin cancer patients with che ^-induced neuropaths pain syndromes. These drugs include dentin. p«g»balin. oxcarbazepine, laniotngine, and felbamate Of anticonvulsants, anecdotal experience has been most favorable ffgabapentin, which is now being widely used by pain specialists to 2 curopathic pain of various types GabapenUn has a relatively high degree Li neuropathic pain c -'safety, including no known drug-drug interactions and a IvV (tl< sei Administration (FDA)-approved for neuropathic pain associated ■v — *■ o ■■•*»-»"*-Muiii aiiu a lack K metabolism." Treatment with gabapentin is usually initiated dose of 300 nig per day and then gradually increased to a dose ranee of hepatic jldostO'-"" -pr-- -y . "j- j"IT"' iu a uoserange Jf «10-3200 mg per day in three divided doses. Pregabalin is Food and pruc Administration (FDA)-approved for neuropathic pain associated with diabetic neuropathy as well as for postherpetic neuralgia A randomized placebo-controlled trial reported by Dworkin et al." demonstrated that pregabalin at doses of 300 mg or 600 mg daily, significantly (educed pain by 30% after 8-week treatment. Oxcarbazepine has shown in small clinical trials to be effective in the management of trigeminal neuralgia and diabetic neuropathy." psychostimulants The psychostimulants dextroamphetamine and methylphenidate are useful antidepressant agents prescribed selectively for medically ill cancer patients with depression." Psychostimulants are also useful in diminishing excessive sedation secondary to narcotic analgesics, and are potent adjuvant analgesics. Bruera et aP' demonstrated that a regimen of 10 mg methylphenidate with breakfast and 5 mg with lunch significantly decreased sedation and potentiated the analgesic effect of narcotics in patients with cancer pain. Dextroamphetamine has also been reported to have additive analgesic effects when used with morphine in postoperative pain.™ In relatively low dose, psychostimulants stimulate appetite, promote a sense of well-being, and improve feelings of weakness and fatigue in cancer patients. Treatment with dextroamphetamine or methylphenidate usually begins with a dose of 2.5 mg at S a.m. and at noon. The dosage is slowly increased over several days until a desired effect is achieved or side effects (overstimulation, anxiety, insomnia, paranoia, confusion) intervene, Typically, a dose greater than 30 mg per day is not necessary although occasionally patients require up to 60 mg per day. Patients dually are maintained on methylphenidate for 1-2 months, and approx-'mately two-thirds will be able to be withdrawn from methylphenidate without a recurrence of depressive symptoms. Those who do recur can « maintained on a psychostimulant for up to 1 year without s>gnin"nt problems. Tolerance will develop and adjustment of dose may oe ntc«sary. A strategy we have found useful in treating cancer pain uso-Cl^d with depression is to start a psychostimulant (starting ° *i in ^ ^ m^ CounlL-ract the sedation tau3t" imctic agent. ™" '"•nagemcm. Modartnil is not a sympatnomimci mechanism of • PA,H 225 issues of aSMSRiS suggest-l«s of a concern with modaSfc -lu "d abuse ^ bc »S™^Y •nnne or methylphenidateS " W',h aSents su^ « dextroamphet NEUROLErT'lCS AND ANTIPSYCHOTIC AGENTS F0R CANCER PAIN BttaSfttaasisthat is -r***,o mor- andSS hi l « ' lt.P,fTideS an alternative aPP">ach in providing « haTntt,mP,?0n0pi0,1,d mechanis^ » is a dopamine blocker and Produc^T ".Tu1 35 aMiol>',ic effec,s- Methotrimeprazine can K-r ""' h>?°tcnsion should be given cautiously by Mow IV mfusion. Unfortunately, methotrimeprazine has limited availability (eg., unavailable in the United States, but available in Canada), umer phenothiazines such as chlorpromazine and prochlorperazine (Compazine) are useful as antiemetics in cancer patients, but probably rrl uu USe 0S analSe5i«'*' Fluphenazine in combination with ICAs has been shown to be helpful in neuropathic pains.107 Haloperidol is the drug of choice in the management of delirium or psychoses in cancer patients, and has clinical usefulness as a co-analgesic for cancer pain.108 Pimozide (Orap), a butyrophenone, has been shown to be effective as an analgesic in the management of trigeminal neuralgia, at doses of 4-12 mg per day.105 Atypical antipsychotics, such as olanzapine, risperidone, quetiapine, apiprazole, and ziprasidone are primarily used to treat delirium in the palliative care setting. Boettger and Breitbart10* suggest that olanzapine and risperidone are the atypical antipsychotics with the most demonstrated efficacy for managing the symptoms of delirium; however, smaller studies and case series reports suggest potential benefit for quetiapine,10* ziprasidone,199 and apiprazole."0 Olanzapine"1 has been used to treat unmanaged pain in the context of anxiety and mild cognitive impairment. Patients received 2.S-7.5 mg of olanzapine daily. Daily pain scores decreased; anxiety and cognitive impairment resolved. Aripiprazole has been shown to be potentially beneficial in reducing bone pain.112 ANXIOLYTIC AGENTS AND CANCER PAIN Hydroxyzine is a mild anxiolytic with sedating and analgesic properties that are useful in the anxious cancer patient with pain."1 This antihistamine has antiemetic activity as well. One hundred milligrams of parenteral hydroxizinc has analgesic activity approaching 8 mg of morphine, and has additive analgesic effects when combined with morphine. Benzodiazepines have not been felt to have direct analgesic properties, although they are potent anxiolytics and anticonvulsants.114 Some authors have suggested that their anticonvulsant properties make certain benzodiazepine drugs useful in the management of neuropathic pain. Recently, Fernandez et al.115 showed that alprazolam, a unique benzodiazepine with mild antidepressant properties, was a helpful adjuvant analgesic in cancer patients with phantom limb pain or deafferentation (neuropathic) pain. Clonazepam (Klonopin) may also be useful in the management of lancinating neuropathic pains in the cancer setting, and has been reported to be an effective analgesic for patients with trigeminal neuralgia, headache, and posttraumatic neuralgia."* With the use of midazolam by IV in a patient-controlled dosage, there was no reduction in the use of postoperative morphine requirements or in the patient's perception of pain.117 Intrathecal midazolam in animal models, however, has been shown to potentiate morphine analgesia.111 CORTICOSTEROIDS Corticosteroid drugs have analgesic potential in a variety of chronic pain syndromes, including neuropathic pains and Pa.n s^dromes Sultins from Inflammatory processes." Like other adjuvant apajg^ cs ortl osteroids are usuauf added to an opioid regimen In patients vith advanced disease, these drugs may also improve appetite, nausea. ORAL LOCAL ANESTHETICS S characterized by cither conl.ni.ouji rUnc, no*Jj > mexi. Smiled trials ^"^^tlÄS cffcCtS fr°m Wnc and there is clinical evidence that wggott «» (akc ( s U to respond adequately to. or who cannot Kith patients with lancinating pains refractory to trials ofanOCOnvu drugs and baclofen. Mexiletine is preferred in the United States. PLACEBO A mention of the placebo response is important to highlight the mis-understandings and relative harm of this phenomenon. The placebo response is common, and analgesia is mediated through endogenous opioids. Ihe deceptive use of placebo response to distinguish psychogenic pain from "real" pain should be avoided. Placebos are effective In a portion of patients for a short period of time only and arc not indicated in the management of cancer pain. REFERENCES 1. Foley KM. The treatment of cancer pain. N Engl I Med. 1985 Jul ll;313(2):84-95. 2. Fitzgibbon DR. Cancer pain: management. In: Loeser ID, Butler SH, Chapman CR. Türk DC (eds). Bonka's management of pain. 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