NEUROLOGICAL REVIEW Advances in Cancer

Kathleen M. Foley, MD

dvances in research and management are an example of the advances that have occurred within the field of neuro-oncology, the medical discipline that includes the diagnosis and treatment of primary central nervous system neoplasms, metastatic and nonmetastatic neurological complications of cancer originating outside the ner- Avous system, and pain associated with cancer. Progress in the diagnosis and treatment of cancer, coupled with advances in our understanding of the anatomy, physiology, pharmacology, and psychology of pain perception, has led to improved care of the patient with pain of malignant origin.1 Currently, specialized methods of cancer diagnosis and treatment provide the most direct approach to treating cancer pain by treating the cause of the pain. Yet, before the introduction of successful antitumor therapy, when treatment of the cause of the pain has failed or when injury to bone, soft tissue, or nerve has occurred as a result of therapy, appropriate is essential. Numerous studies support the observa- tive information has helped to frame a sci- tion that patients with cancer pain are best entific rationale for the use of new and treated with a multidisciplinary ap- improved methods of cancer pain treat- proach using the expertise of a wide range ment. A brief review of the basic research of health care professionals.2 The goal of advances in the neuroanatomy, physiol- such pain therapy for patients receiving ac- ogy, and pharmacology of pain provides tive treatment is to provide them with suf- a background for discussing the ad- ficient relief to tolerate the diagnostic and vances in clinical pain management. De- therapeutic approaches that are needed to tailed information now supports the theory treat their cancer. For patients with ad- that activation of peripheral receptors in vanced disease, pain control should be suf- both superficial and deep structures as well ficient to allow them to function at a level as viscera by mechanical and chemical they choose and to die relatively free of stimuli excites afferent discharges. Non- pain. The management of the symptom nociceptive messages are transmitted pain should be only one component of a through rapidly conducting A-␤ fibers, and broad palliative care approach for pa- nociceptive information is signaled tients with cancer. Control of other symp- through slowly conducting A-␦– and C- toms, treatment of psychological dis- fiber afferents. The receptor endings of A-␦ tress, and attention to the religious, fibers most often respond to one sensory spiritual, and existential dimensions of the stimulus, whereas most C-fiber receptors patient’s illness experience should be con- are multimodal and respond to multiple currently addressed to maintain the pa- high-threshold stimuli. These primary sen- tient’s quality of life throughout the can- sory afferents have their cell bodies in the cer illness from diagnosis to death.1 dorsal root ganglion, and their axons en- ter the spinal cord via the dorsal root. The ADVANCES IN CANCER PAIN: synaptic connections of these primary af- BASIC RESEARCH ferents with the corresponding second- order nociceptive neurons in the spinal Extensive information about ascending and dorsal horn are the initial site of process- descending central nervous system path- ing for sensory information, and act as a ways that process and modulate nocicep- relay in transmitting noxious signals to the central nervous system. They ascend or de- From the Departments of Neurology, Memorial Sloan-Kettering Cancer Center and scend from 1 or 2 segments in the dorso- Cornell University Medical College, New York, NY. lateral fasciculus and synapse in specific

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©1999 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 lamina in the dorsal horn: lamina I and lamina II. Evi- ceptors including high- and low-affinity µ receptors and ␥, dence suggests that myelinated project to ␬, and ␦ receptors are localized to specific areas of the brain, laminae I and V, unmyelinated nociceptors to lamina II spinal cord, and peripheral nervous system. More recently, and possibly lamina I, and nonnociceptive myelinated af- severalopioidreceptorsubtypeshavebeencloned,andquan- ferents only to deep laminae. titative changes in the messenger RNA for these receptors The dorsal horn is a critical site for modulating sen- have been determined in experimental models. The clon- sory input, and recent studies have elaborated the mo- ingofthesesubtypesofreceptorsthatmediatedifferentphar- lecular biology and pharmacology of pain modulation at macological effects and are then located in specific cerebral, this site. Sensory transmission is mediated through neu- spinal, and peripheral sites offers the possibility of devel- ropeptides, , calcitonin gene–related pep- oping new targeted for specific receptors. For ex- tide, and the excitatory amino acids (EAAs), both glu- ample, µ receptors modulate predominantly supraspinal an- tamate and aspartate. Excitatory synaptic transmission algesia, whereas ␦ and ␬ receptors are important in modu- from the primary afferent is modulated by the N-methyl- lating analgesia at the spinal cord level. The periaqueductal D-aspartate (NMDA) receptor as well as non-NMDA re- gray region in the midbrain and the dorsal horn in the spi- ceptors. After EAA-NMDA receptor interaction, intra- nal cord are rich in these receptors and are the supraspinal cellular calcium influx and mobilization of intracellular and spinal sites that mediate opioid analgesia. The use of calcium lead to subsequent changes in second- brainstem and spinal cord stimulation and the administra- messenger systems. Protein kinase C modulates these ac- tion of opioid analgesics directly into the cerebrospinal fluid, tivities. One second messenger system that is activated bathing the selective opioid sites in patients with cancer who after EAA-NMDA receptor interaction is the generation are in pain, are procedures based on this knowledge. Pain of nitric oxide via the enzyme nitric oxide synthase. There transmission at the spinal cord level can be inhibited by the is also an increase in transcription of immediate early gene direct application of morphine onto the spinal cord, and c-fos, which may regulate the subsequent expression of these studies have led to the use of spinal opioid analgesia endogenous opioid genes, preproenkephalin and pre- in clinical pain states. prodynorphin. The receptor activation of NMDA ini- There is now increasing information about the mo- tiates and maintains central sensitization and the com- lecular basis of opioid tolerance development. A variety ponent known as windup. These phenomena are of NMDA receptor antagonists have now been demon- manifestations of persistent signaling from primary sen- strated to both attenuate and reverse experimental opi- sory afferents. Central sensitization is thought to be the oid tolerance. Therefore, the confluence of major mechanism underlying neuropathic pain, and NMDA receptors in pain transmission and in the devel- accounts for the hyperpathia and enlarged cutaneous opment of tolerance has provided new insights into the receptor fields that occur after nerve injury.3 role of opioid receptors in analgesia. At the level of the second-order neurons in the dor- These advances in our understanding of pain modu- sal horn, sensory processing occurs through interactions latory systems and their neuroanatomical and neurophar- among neurochemical transmitters released by primary macological correlates have had a major impact on the treat- afferents including ␥-amino butyric acid, glycine, adeno- ment of patients with cancer pain. A better understanding sine, bombesin, cholecystokinin, dynorphin, enkepha- ofthemolecularbiologyof bothnociceptiveandneuropathic lin, neuropeptide Y, neurotensin, substance P, somato- pain is facilitating the wide application of a variety of agents, statin, and vasoactive intestinal polypeptide. Several both opioid and nonopioid, to treat cancer pain. ascending pathways arise from these second-order neu- rons and decussate in the central gray of the spinal cord ADVANCES IN CLINICAL CANCER PAIN: to become the neospinothalamic and paleospinothalamic CLINICAL MANAGEMENT tracts. These tracts project to discrete regions of the thala- mus and cortex. The neospinothalamic pathway sub- Increased attention for the need to develop a public health serves pain intensity and localization, whereas the phy- program to provide cancer pain management has created logenetically older paleospinothalamic pathway subserves the impetus to define the epidemiology and ethnography the arousal and emotional component of pain. of cancer pain. These studies demonstrate that one third Descending pathways, the most important of which of the adult patients with cancer who are in active therapy originate from the periaqueductal gray nuclei of the mid- and two thirds of the patients with advanced disease have brain, synapse in the raphae magnus nucleus of the me- significant pain.1 The prevalence of pain increases with dis- dulla. From this nucleus, a medial pathway, the dorsal ease progression, and the intensity, type, and location of longitudinal fasciculus, projects to the dorsal horn to the pain vary according to the primary tumor site, extent modulate pain transmission. This pathway represents an of disease, and treatments used. Multiple causes and sites important descending inhibitory pathway. A more lat- of pain are common, with up to 81% of patients reporting erally placed descending pathway from the locus ce- 2 or more distinct complaints and 34% reporting 3 types ruleus to the dorsal horn also plays a role in pain modu- of pain. In the landmark study of 1308 oncology patients lation at the spinal cord level. followed up by the Eastern Cooperative Oncology Group, Opiate receptors, stereospecific binding sites on the 56% of patients reported moderate to severe pain 50% of end of free nerve endings that bind exogenous opioids, are the time.4 Multiple reviews have demonstrated that pain localized in the ascending and descending pain pathways. associated with direct tumor involvement is the most com- These receptors mediate the multiple pharmacological ef- mon cause of cancer pain, occurring in upwards of 85% fects of the opioid analgesics. Subpopulations of opioid re- of patients on inpatient pain services and up to 65% of pa-

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©1999 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 tients seen in outpatient pain clinics. is the most controlled analgesic pumps; they have also helped to bet- common type, with tumor infiltration of nerve and hol- ter define the role of opioids’ active metabolites. For ex- low viscus as the second and third most common pain lo- ample, studies of morphine and its active metabolite cations. Pain is the most frequent symptom in patients with morphine-6-glucuronide have been performed using these neurological complications of cancer. Pain associated with techniques.7 Because of the results of these studies, mor- cancer therapy occurs in upwards of 15% to 25% of pa- phine-6-glucuronide is recognized as a potent analgesic tients who undergo surgery, radiation therapy, or chemo- with a much longer half-life (12-14 hours) than mor- therapy. Three percent to 10% of patients have pain caused phine (3-4 hours). Morphine-6-glucuronide is cleared by by noncancer-related problems. In children with cancer, the kidney and accumulates in patients with compro- pain is commonly associated with procedures and is re- mised renal function. Using both pharmacokinetic and ported to occur in up to 60% of children who receive ac- pharmacodynamic data, the pharmacokinetics of cere- tive therapy. Detailed reviews have defined the common brospinal fluid distribution of opioid drugs has facili- neurological and nonneurological pain syndromes in pa- tated the development of dosing algorithms for both epi- tients with cancer and have outlined specific evidence- dural and intrathecal opioid administration.6 In short, based algorithms for their evaluation and treatment. these advances in the clinical pharmacological aspects of Concurrent with increased knowledge of the com- opioids have facilitated a better understanding of and sci- mon pain syndromes have been advances in the devel- entific guidelines for the use of opioid analgesics by novel opment of analgesic assays to measure acute, chronic, and routes of drug administration, including transmucosal, experimental pain in patients with cancer. Validated an- transdermal, epidural, intrathecal, and intraventricular algesic assay methods using sophisticated measurement routes. Such pharmacokinetic-pharmacodynamic mod- instruments, new study designs, and innovative statisti- els have again helped to develop and provide clinically cal analyses have facilitated acute and stud- relevant scientifically based guidelines for the use of slow- ies.5 Several instruments, including the Brief Pain Inven- release preparations, which are commonly used for pain tory, the Memorial Pain Assessment Card, the Memorial management in patients with cancer and are currently Symptom Assessment Scale, and the Edmonton Symp- available for morphine, hydromorphone, and oxy- tom Assessment Scale, have facilitated repeated measure- codone and for fentanyl by the transdermal route. ments over time that allow a correlation of pain inten- sity with functional activity and quality of life.2 These validated methods have provided the tools to study pain NCREASED ATTENTION has been focused on the interventions and outcomes of therapy not only of an- need to maximize analgesia and to minimize ad- algesic agents’ but also of chemotherapeutic and radia- verse effects, and there have been advances in our tion therapy protocols’ impact on pain. understanding of the role of various adjuvant an- The unique development of new paradigms of hu- algesics in cancer pain management.1,3 These ad- man experimental pain using intradermal capsaicin and vancesI have led to a better understanding of (1) the role specific nociceptive stimuli, coupled with neurophysi- of the tricyclic antidepressants and selective serotonin ological and psychophysical methods, has allowed the reuptake inhibitors in neuropathic pain; (2) the role of testing of potentially new agents that have an impact both methylphenidate in treating the sedative effects of opi- on the development of windup and on central sensitiza- oids; (3) the safety and efficacy of haloperidol to man- tion, the important neurophysiological components of age opioid- and steroid-induced delirium; (4) the effi- nerve injury. The availability of these new human ex- cacy of corticosteroids in treating in patients perimental neuropathic pain paradigms provides the op- with brain metastases, in patients with epidu- portunity for the rapid assessment of new agents. By com- ral cord compression, and bone pain in patients with meta- bining these analgesic assay methods with functional static prostate cancer; (5) the use of topical local anes- magnetic resonance imaging and positron emission to- thetics (eg, Emla cream) to reduce pain after venous or mography, further insights into the central mechanisms arterial catheterization, lumbar puncture, and bone mar- of pain modulation and the distinctions between the com- row aspiration; (6) the use of bisphosphonates in reduc- ponents of perception and affective responses have been ing bone pain in patients with multiple myeloma and identified.6 In short, the expanding analgesic assay meth- breast cancer8; and (7) the role of gabapentin in periph- ods have created new opportunities to better under- eral neuropathy and postherpetic . stand the central and peripheral mechanisms of pain in Notwithstanding these advances, cancer pain is dif- patients with cancer. ficult to manage and neuropathic pain remains a major chal- At the same time, advances in clinical pharmacol- lenge. Numerous pilot studies and case reports have been ogy characterized by the availability of specific and sen- published recently that suggest the potential role of a wide sitive methods to analyze opioids and peptides in plasma variety of adjuvant analgesics in managing neuropathic and cerebrospinal fluid and to correlate these drug lev- pain.3 These analgesics include anticonvulsants (eg, car- els to pharmacodynamic effects have led to the develop- bamazepine, baclofen, and valproic acid), oral local anes- ment of pharmacokinetic-pharmacodynamic models.5 thetics (eg, mexiletine hydrocloride), neuroleptics (eg, Such models are particularly useful in achieving a better pimozide), and peptides (eg, calcitonin). To date, the lack understanding of drug distribution and elimination and of well-controlled trials limits the development of evidence- have been specifically used to design appropriate drug- based guidelines. Empirical use of these drugs in sequen- dosing regimens for patients with cancer. These studies tial drug trials is suggested to manage intractable pain in have served as the underpinnings for the use of patient- patients with cancer.

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©1999 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 As previously mentioned, recent attention has focused onstrated that tolerance develops at different rates to each on NMDA receptors and their role in neuropathic pain. of the opioid’s effects. Tolerance development to the res- Both ketamine and dextromethorphan have been shown piratory depressant effects of opioids has provided pro- to provide pain relief in patients with cancer. Studies of tection to patients with cancer as they escalate their doses dextromethorphan in combination with morphine have to obtain improved analgesia. These studies in patients shown increased analgesic effects as compared with mor- with pain demonstrate that changes in the pain stimu- phine alone. Ketamine, commonly used as an anesthetic, lus, ie, progression of tumor in patients with cancer pain, hasbeenshowntoproduceanalgesiainsubanestheticdoses. are the most common cause for dose escalation. With Animal studies of ketamine and dextromethorphan have chronic pain, stable doses of opioids can provide con- demonstrated the ability of these drugs both to prevent tinuous pain relief for long periods of time without dose the development of neuropathic pain and to limit the de- escalation. Cross-tolerance is not complete among the opi- velopment of tolerance. Increased attention is now focus- oids used in clinical practice, and analgesia can be ob- ing on the clinical aspects of these drugs and their role in tained by switching to an alternative opioid. Opioid ro- managing neuropathic pain in patients with cancer. tation provides the opportunity to maximize analgesia and The results of recent studies of methadone, a com- to minimize adverse effects. It is particularly interesting monly used second-line opioid analgesic to manage can- to note that there appears to be no limit to tolerance and cer pain, suggest that methadone may provide analgesia that large doses can be used to provide analgesia with mini- through both an opioid and a nonopioid mechanism.9 Ani- mal adverse effects. Physician concern that the develop- mal studies indicate that methadone may be different from ment of analgesic tolerance limits the chronic use of opi- other µ opioids, such as morphine, hydromorphone, and oids has not been validated in clinical studies in patients oxycodone, because the d- and the l-isomers of metha- with cancer pain. A better understanding of the role of done’s racemic mixture bind to the NMDA receptor. Ani- NMDA antagonists in preventing the development of tol- mal studies show that d-methadone is weak or inactive erance offers the opportunity to enhance analgesia and to as an opioid but is antinociceptive in a neuropathic pain maintain stable doses over long periods. model as an antagonist at the NMDA receptor. These stud- ies suggest that methadone analgesia may result in part Psychological Dependence from the d-isomer potentiating the opioid antinocicep- tive effect of l-methadone. The NMDA receptor antago- Fear of addiction continues to be a barrier to the wide- nists attenuate the development of morphine; therefore, spread use of opioids for cancer pain management. Expe- d-methadone may also act to attenuate the tolerance to rience with large numbers of patients treated for cancer the opioid components of racemic methadone. pain with opioids has demonstrated that there is a negli- These advances in the basic and clinical aspects of gible risk of psychological dependence. Increased opioid analgesic drug therapy have led to a redefinition of our availability is not associated with increased illegal drug traf- understanding of the concepts of opioid responsive- ficking or recreational use. Patients with cancer who take ness, tolerance, and psychological dependence.1,10 These opioids chronically will develop physical dependence, new insights have facilitated a broader use of opioids in which can be precipitated by abrupt drug withdrawal. With both cancer and non-cancer–related pain syndromes. effective pain management, patients commonly reduce their opioid doses, and their drug use should be slowly ta- Opioid Responsiveness pered to prevent the appearance of a withdrawal state. Despite these important advances in our knowledge It is now well recognized that opioids provide analgesia about cancer pain, large numbers of patients remain in- over a continuum and that neuropathic pain is less respon- adequately treated according to recently published sur- sive to opioid drug therapy. This conceptual framework veys of patients with cancer who have serious life- has important clinical implications, as it is the basis for threatening illness, patients in nursing homes, and patients the major pharmacological principle of “dosing to effect.” with cancer in outpatient oncology clinics. The elderly, Each patient should be given a trial of an opioid titrated minorities, and women are most affected by this under- to limiting adverse effects to determine the opioid’s effi- treatment of pain. The lack of integration of this exten- cacy in treating a particular type of cancer pain. Such an sive database to manage cancer pain into undergraduate approach has demonstrated that somatic, visceral, and neu- and graduate medical education is a major “systems” bar- ropathic pain responds in a variable manner to opioids and rier to effective treatment of cancer patients with pain. There that sequential clinical trials are the only approach to de- is an urgent need to institute into practice what we know termine opioid dose and efficacy for an individual patient. now, as it can provide pain relief to large numbers of pa- tients with cancer. Widespread attention to this need has Tolerance led to the development of state-based cancer pain initia- tives created as grass roots organizations to advocate for Tolerance is the term that is used to describe a reduced patients’ rights for adequate treatment of their pain symp- effect of a drug as a consequence of its prior administra- toms. Professional organizations need to mandate educa- tion. The chronic use of opioids in the patient with can- tion in cancer pain management to bring these important cer pain has provided a natural experiment to show that advances to the patients who need them. tolerance is not a limiting factor to the long-term use of opioids.11 Studies of the long-term use of opioids in pa- Accepted for publication December 18, 1998. tients with cancer pain over the last 25 years have dem- Reprints not available from the author.

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©1999 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 6. Craig AD, Reiman EM, Evans A, Bushnell MC. Functional imaging of an illusion REFERENCES of pain. Nature. 1996;384:217-218. 7. Portenoy RK, Thaler H, Inturrisi C, Friedlander-Klar H, Foley KM. The metabolite 1. Foley KM. Management of cancer pain. In: Devita VT, Hellman S, Rosenberg SA, morphine-6-glucuronide contributes to the analgesia produced by morphine in- eds. Cancer: Principles and Practice of Oncology. 5th ed. Philadelphia, Pa: Lip- fusion in patients and normal renal function. Clin Pharmacol Ther. 1992; 51: pincott-Raven Publishers; 1997:2807-2841. 422-431. 2. Foley KM. Pain assessment and cancer pain. In: Doyle D, Hanks GW, Macdonald 8. Pereira J, Mancini I, Walker P. The role of bisphosphonates in malignant pain: a RN, eds. Oxford Textbook of Palliative Medicine. New York, NY: Oxford Univer- review. J Palliat Care. 1998;14:25-36. sity Press Inc; 1993:148-166. 9. Foley KM, Houde RW. Methadone in cancer pain management: individualize dose 3. Moulin DE, Jadad AR, Hewitt DJ, et al. Review of neuropathic pain. In: Bruera E, and titrate to effect. J Clin Oncol. 1998;16:3212-3214. Portenoy RK, eds. Topics in Palliative Care. Vol 2. New York, NY: Oxford Uni- 10. Cherny NI, Chang V, Frager G, et al. Opioid pharmacotherapy in the manage- versity Press Inc; 1998:3-86. ment of cancer pain: a survey of strategies used by pain physicians for the 4. Von Roenn JH, Cleeland CS, Gonin R, Hatfield AK, Pandya KJ. Physician atti- selection of analgesic drugs and routes of administration. Cancer. 1995;76: tudes and practice in cancer pain management: a survey from the Eastern Co- 1288-1293. operative Oncology Group. Ann Intern Med. 1993;119:121-126. 11. Foley KM. Changing concepts of tolerance to opioids: what cancer pain has taught 5. Max MB, Portenoy RK, Laska E, eds. The Design of Analgesic Clinical Trials: Ad- us. In: Chapman CR, Foley KM, eds. Current and Emerging Issues in Cancer Pain: vances in Pain Research and Therapy. Vol 18. New York, NY: Raven Press; 1991. Research and Practice. New York, NY: Raven Press; 1993:331-349.

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