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Effective treatment of severe cancer pain of the head using low-dose ketamine in an opioid-tolerant patient
310 Journal of Pain and £~mptom Management
Vol. 10 No. 4 May 1995
Palliative Care Rounds
Effective Treatment of Severe Cancer Pain of the Head Using Low-Dose Ketamine in an Opioid-Tolerant Patient J o h n L. Clark, MD, a n d Gary. E. Kalan, MD Department of Anesthesiolo~, Greenwich Hospital, Greenwich, Connecticut
Abstract We report the ~z~se of a 39-year-oM man with severe pain due to unresectable squamous-cell carcinoma of the maxillary,' sinus that had invaded cranial bone and had metastasized to the cervical spine. Tolerance to opioids had developed, and high doses of transde~vnal, continuous intravenous, and epidural opioids did not control his pain. An acute episode of extremely severe head pain was immediately controlled with a subanesthetic dose of ketamine after failure of a stress dose of corticosteroid and intravenous lidocaine. Because the patient was terminally ill and invasive procedures were not options, we controlled his pain using a low-dose ketamine infusion until his death 13 dm, s later. Ketamine may be a good co-analgesic/or breakthwugh pain and for severe pain caused by terminal cancer when invasive techniques are inappropriate. Its mechanism of action may include reversal of opioid tolerance in addition to an inherent analgesic effect. J Pain Symptom Manage 1995;10:310-314.
Key Words Cancer pain, breakthrough pain, pain management, ketamine, opioid, tolerance, N-methylD-aspartate receptor
Patients with severe cancer pain may be very difficult to manage. In the terminal stage of disease, radiotherapy, surgery, and c h e m o t h e r apy will no longer be effective, and patients may b e c o m e tolerant to potent opioids. If intravenous infusion of opioids or intraspinal administration of opioids, with or without adjuvant drugs, do not control the pain, neuroablative procedures may be necessary.t Neuroablative procedures may be a p p r o p r i a t e in
Address reprint requests to:John L. Clark, MD, Greenwich AnesthesioloD, Associates PC, PO Box 772, Greenwich, CT 06836, USA. Acceptedfor publication: September 22, 1994. © U.S. Cancer Pain Relief C;ommittee, 1995 Published by Elsevier, New York, New York
major medical centers; they may not be available in c o m m u n i t y hospitals. We r e p o r t a case of a patient with terminal cancer of the maxillary sinus who e x p e r i e n c e d extremely severe acute pain while being treated with high doses of transdermal, continuous intravenous, and continuous intraspinal opioids. At the m o m e n t of crisis, a subanesthetic dose of ketamine was administered empirically, and the patient e x p e r i e n c e d dramatic relief of pain. Thereafter, we were able to manage his pain pharmacologically with low-dose ketamine and opioids. We speculate that ketamine was effective because it is analgesic in low doses and because it may have reversed opioid tolerance in our patient. We r e c o m m e n d that 0885-3924/95/$9.50 SSDI 0885-3924(95)00010-V
VoL 10 No. 4 May 1995
Ketamine ]br Severe Cancer Pain
ketamine be considered as an adjuvant drug in certain patients with severe cancer pain.
Case Report A 39-year-old man developed pain due to recurrent squamous-cell carcinoma of the maxillary sinus that was resistant to chemotherapy and radiation therapy. Fifteen months prior to admission, carcinoma of the left maxillary sinus was diagnosed, and he underwent left maxillectomy, anterior and posterior ethmoidectomy, and radiation therapy. T h e r e was no evidence of invasive disease. Nine months prior to admission, the patient complained of sinus pain, and r e c u r r e n t tumor destroying the lacrimal bone was diagnosed. The patient underwent craniofacial resection. Subsequent chronic pain of the left face and orbit was treated with trigeminal nerve block. These procedures were carried out at a major medical center. Four months prior to admission, recurrent tumor was again diagnosed. Surgery was no longer possible, and the patient was treated with high-dose chemotherapy using cis-platin u m and 5-fluorouracil. The tumor progressed to involve the left orbit and metastasized to the body of C2. T h e patient was treated at h o m e with intravenous nutrition, transdermal fentanyl, and subcutaneous levorphanol until he was admitted to our hospital because of weakness and a change in mental status secondary to hypercalcemia. Intravenous fluid and pamidromate therapy reversed the hypercalcemia, and his mental function returned to normal. He complained of neck and facial pain. Cervical spine radiographs showed destruction of the C2 vertebral body. His neck was stabilized with a collar. The left side of his face was distorted from swelling due to inflammation and tumor growth, and he wore a patch over his left orbit. The goal of therapy was to control his pain so that he could return home. On admission, his pain was managed with transdermal fentanyl totalling 400 p g / h r and levorphanol 2-4 mg subcutaneously every 2 hr. He refused radiation therapy as a m e t h o d of pain control. During the first week his face and neck pain worsened rapidly, and his opioid requirement increased to fentanyl 1600 p g / h r transdermally and levorphanol 12 mg subcutaneously ever}, 2
311
hr. Dexamethasone, 4 mg intravenously (IV) every 8 hr, briefly reduced his pain. The anesthesia service was consulted after his second week o f hospitalization because his pain was not controlled with fentanyl 1600 g g / hr, levorphanol infusion 30 m g / h r plus 15-rag bolus doses for breakthrough pain, and supplemental lorazepam 1 mg intravenously every 4 hr for anxiety. Initial consideration was given to converting the patient to a continuous intravenous fentanyl infhsion, but this was not possible due to the high doses required by the patient and a limited supply of fentanyl. An epidural catheter was inserted to increase cerebrospinal fluid levels of opioid by the intraspinal route. A 5 mg bolus of epidural m o r p h i n e was given followed by a continuous epidural m o r p h i n e infusion at 0.4 rag/hr. Levorphanol was increased to 40 m g / h r IV. His level of pain decreased slightly over the next 24 hr, then worsened. During the second day of epidural m o r p h i n e therapy, the levorphanol infusion was replaced with a continuous m o r p h i n e infusion that was titrated up to 120 m g / h r and supplemented with 10-15 nag boluses for breakthrough pain. Transdermal fentanyl was continued at 1600 p g / h r , and anxiety was treated with midazolam 1-2 mg IV as needed. During the third day of epidural m o r p h i n e therapy, his pain worsened, and the infusion rate was increased to 0.8 m g / h r , then to 1 r a g / hr. T h e patient acutely developed a severe headache. The intravenous m o r p h i n e infusion was increased to 240 m g / h r , supplemented with 30 mg IV boluses. An intracranial hemorrhage was suspected, and the patient was given mannitol 1.5% 50 cc IV and dexamethasone 100 mg IV for increased intracranial pressure. This was not effective. T h e patient clutched his head and started screaming. The oncologist requested an urgent anesthesia consultation for pain control. Lidocaine 100 mg IV was first administered but had no beneficial effect. Next a subanesthetic dose of ketamine, 50 mg IV, was given, which promptly relieved his pain. T h e patient relaxed, stopped clutching his head, and smiled. After 30 min, his head pain returned. The patient was alert e n o u g h to say the effect of the drug was acceptable and asked that it be given again. Ketamine 25 mg IV and 100 mg ketamine intramuscularly (IM) were
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given for pain control until an infusion could be prepared. A rate of 100 m g / h r was chosen for analgesia because the first dose of 50 mg had an effect lasting about 30 min. During the first 24 hr, treatment for b r e a k t h r o u g h pain was required only once. On the second day of ketamine infusion therapy, the epidural catheter was removed. On the third day of therapy, the transdermal fentanyl was discontinued while the IV infusion of m o r p h i n e was continued at 330 m g / h r . T h e patient r e m a i n e d comfortable, and no additional m o r p h i n e was required for b r e a k t h r o u g h pain. He was able to sleep at night. Although sedated, his wife was able to speak to him at times, and he recognized his b r o t h e r who had traveled f r o m J a p a n to be with him. T h e patient ultimately developed p n e u m o nia. A c e t a m i n o p h e n was used to reduce fever. However, the patient a p p e a r e d agitated to his family and nurses. T h e r e was concern that he was again suffering pain, and the oncologist o r d e r e d increases in the drug-infusion rates. Doses of m o r p h i n e 1000 m g / h r , midazolam 12 m g / h r , and ketamine 200 m g / h r were reached before the patient expired on day 13 of continuous ketamine infusion.
D/seuss/on O u r patient e x p e r i e n c e d moderate-to-severe pain, a c o m m o n experience r e p o r t e d by 6 0 % 90% of patients with advanced cancer.l Most of these patients can be m a n a g e d with pharmacologic therapy using the World Health Organization (WHO) three-step "analgesic ladder," which progresses from n o n o p i o i d analgesic therapy to " s t r o n g " opioid therapy with or without adjuvant drugs. 2':~ The W H O recomm e n d s m o r p h i n e as the drug of choice for severe cancer pain because of its frequent use and wide availability. The W H O regimen has been validated by Ventafridda and associates in a retrospective study of patients with advanced or terminal cancer. 3 Pharmacologic therapy may fail to control severe cancer pain. O u r patient fits into a category of patients described by Coyle and colleagues, whose pain could not be relieved despite changing opioids, combining opioids, using high doses of opioids, and administering these drugs by all available routes. 4 A n o t h e r
Vol. 10 No. 4 May 1995
p r o b l e m was that we could not evaluate the exact etiology of o u r patient's pain at the time of crisis. T u m o r s of the paranasal sinuses are known to cause severe pain because of direct invasion of the base of the skull and t u m o r involvement of nerves. 1 O u r patient may have e x p e r i e n c e d lancinating pain in the distribution of the trigeminal nerve. In a major medical center, neurosurgical ablative techniques, neurolytic gasserian ganglion block, and intraventricular opioids might have b e e n options, but we were limited to a pharmacologic approach in an acute situation without an exact diagnosis. T h e initial a t t e m p t to achieve analgesia with a bolus dose of lidocaine was based u p o n reports that this had b e e n effective in the relief of both vascular headaches and central pain syndromes. ~'6 The p r o p o s e d mechanisms include local inhibition of nociceptive trigeminal afferents that innervate cranial blood vessels and a central effect that decreases spontaneous burst activity of abnormally active neurons. Ketamine hydrochloride was chosen empirically because it is a general anesthetic that is effective in subanesthetic doses with a very low risk of respiratory depression. It is an arylcycloalkylamine similar to phencyclidine hydrochloride (PCP) and is used to create a state of "dissociative anesthesia." While receiving this drug, the patient may cry out and move in response to a painful stimulus but has no awareness of the pain. 7,s Ketamine is most effective as an anesthetic for somatic pain; it is not as effective against visceral pain. A benzodiazepine is usually given along with ketamine to prevent unpleasant psychic disturbances, such as unpleasant dreams, delirium, and hallucinations. 7 Like m o r p h i n e , ketamine is an inexpensive, widely available drug that has b e e n used for analgesia and anesthesia u n d e r adverse conditions, including mass casualties during wartime and in developing countries where trained anesthetists are not available. 9 It is supplied as a racemic mixture of two optical isomers, chiral forms (S)ketamine and (R)-ketamine, in 1%, 5%, and 10% solutions. Ketamine's m e c h a n i s m of action has not been fully explained. Recent studies 1°'11 suggest that its analgesic and anesthetic actions are explained by blockade of the N-methyl-D-aspar-
Vol. 10 No. 4 Mm, 1995
Ketamine for Severe Cancer Pair~
tate (NMDA) receptor. The NMDA receptor is one type of receptor for excitatory amino acids, such as L-glutamate and L-aspartate, which may be important in nociceptive sensor?" transmission. 1° In a study by Oye and coworkers, the chiral forms of ketamine were used as probes for NMDA receptor-mediated neurotransmission. 1~ (S)-ketamine was four times as potent as (R)-ketamine in reducing pain perception and in causing auditory and visual disturbances, and both caused dissociative disturbances in the form of feelings of d e t a c h m e n t from the body. Both forms of ketamine displaced a non-competitive NMDA receptor antagonist (MK801) from specific binding sites in membrane fractions of brain homogenates. These findings indicated that inhibition of sensor}; perception by subanesthetic doses of ketamine is due to PCP site-mediated noncompetitive blockade of NMDA receptor operated channels. For induction of general anesthesia in the adult, ketamine is administered in an intravenous dose of 1-3 m g / k g over 1 min or in a dose of 6.5-13 m g / k g IM. s Because of its psychic effects, it is rarely used in anesthetic doses. Instead, it is used in subanesthetic doses to provide analgesia for a variety of purposes. Slogoff and coworkers r e c o m m e n d e d a dose of 1.5 m g / k g IM to provide 15 min of analgesia for burn dressing changes, 1~ and Akamatsu recomm e n d e d 0.2-0.4 m g / k g IV to provide safe, brief analgesia for vaginal delivery', l~ Sadove and colleagues found that ketamine 0.44 m g / kg IM provided effective analgesia for postoperative pain lasting up to 60 rain with most patients experiencing only dizziness and pleasant psychic effects. 14 InflLsion of midazolam 0.05-0.15 m g / k g IV followed by low-dose ketamine 0.25-0.5 m g / k g 1V provides safe intravenous conscious sedation without respiratoo' depression during outpatient cosmetic surgery u n d e r local anesthesia. 1"~' Oshima and associates reported that continuous low-dose subcutaneous ketamine at 2.5-15 m g / h r was effective in providing analgesia in 13 of 18 terminal cancer patients who were refractor)' to opioids. 16 A recent study by Roytblat and colleagues examined the effect of low-dose ketamine in addition to general anesthesia on postoperative pain. 17 They gave patients in the study group ketamine 0.15 m g / k g IV 5 rain before
313
surgical incision and observed a reduced dose r e q u i r e m e n t for m o r p h i n e in the first 24 hr postoperatively. They suggested that ta-opioid agonists such as m o r p h i n e and fentanyl act synergistically with the NMDA receptor antagonist ketamine hydrochloride. Our patient received ketamine 50 mg IV initially, or 0.92 m g / k g based on his weight of 54.5 kg. This is a high dose when compared to the doses used in the above reports, but our patient never became anesthetized, and we were able to speak with him during the period when his pain was relieved. On the basis of this clinical experience, lowdose ketamine therapy appears to be safe. This drug is an anesthetic, however, and has the potential for loss of consciousness, airway obstruction, and respiratory depression. Therefore, ketamine therapy should be titrated, starting with very small doses, such as 5-10 mg by IV bolus or 0.1-0.2 m g / k g / h r by infusion. Equipment for airway m a n a g e m e n t should be readily available. Recent work by Tiseo and Inturrisi using laboratory animals indicates that N-methyl-D-aspartate receptor antagonists can attenuate and reverse m o r p h i n e tolerance, is A noncompetitive NMDA antagonist MKS01 and a competitive antagonist LY274614 were studied. Both agents significantly attenuated the development of m o r p h i n e tolerance when given simultaneously with morphine. Treated animals seemed to maintain their sensitivity to morphine for 1 week after therapy was stopped in contrast with the control animals, and LY274614 restored m o r p h i n e sensitivity in tolerant animals. Because MK801 and other noncompetitive NMDA antagonists produce PCPlike behavior in animals, these authors r e c o m m e n d that competitive NMDA antagonists, such as LY274614, be developed as adjuncts for patients receiving chronic opioids for pain m a n a g e m e n t because they lack phencyclidine-like side effects. Ketamine is a noncompetitive NMDA antagonist, which may have reversed opioid tolerance in our patient. The dramatic pain relief after a subanesthetic dose of ketamine may be explained, therefore, by the analgesic effects of low-dose ketamine, the synergism of ketamine and morphine, and the reversal of tolerance, which could have allowed our patient to experience the full analgesic and euphoric effects of
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o p i o i d therapy. Until a m o r e specific N M D A r e c e p t o r antagonist b e c o m e s available, we believe that k e t a m i n e may be used in subanesthetic doses as an a d j u n c t or coanalgesic in opioid tolerant patients e x p e r i e n c i n g severe c a n c e r pain.
R•• 1. Bonica JJ. The management of pain. Philadelphia: Lea and Febiger, 1990:400--460, 804-809. 2. World Health Organization (WHO). Cancer pain relief. Geneva: WHO, 1986:19. 3. Ventafridda V, Tamburini M, Caraceni A, De Conno F, Naldi F. A validation study of the WHO method of cancer pain relief. Cancer 1987;59:850856. 4. Coyle N, Adelhardt J, Foley KM, Portenoy RK. Character of terminal illness in the advanced cancer patient: pain and other symptoms during the last four weeks of life. J Pain Symptom Manage 1990;5: 83-93. 5. Maciewicz R, Chung RY, Strassman A, Hochberg F, Moskowitz M. Relief of vascular headache with intravenous lidocaine: clinical observations and a proposed mechanism. Clin J Pain 1988;4:11-16. 6. Backonja M, Gombar K. Response of central pain syndromes to intravenous lidocaine.J Pain Symptom Manage 1992;7:172-178. 7. Jaffe JH. Drug addiction and drug abuse. In: Goodman AG, Rall TW, Nies AS, Taylor P, eds. Goodman and Gilman's the pharmacologic basis of therapeutics. New York: Pergamon, 1990:557-558. 8. Marshall BE, Longnecker DE. General anesthetics. In: Goodman AG, Rall TW, Nies AS, Taylor P, eds. Goodman and Gilman's the pharmacologic ba-
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sis of therapeutics. New York: Pergamon, 1990:306307, 9. Atkinson RS, Rushman GB, Lee JA. A synopsis of anesthesia. Bristol: IOP, 1987:247-250. 10. Yamamura T, Harada K, Okamura A, Kemmotsu O. Is the site of action of ketamine anesthesia the N-methyl-D-aspartate receptor? Anesthesiology 1990; 72:704-710. 11. Oye I, Pausel O, Maurset A. Effects of ketamine on sensory perception: evidence for a role of n-methyl-d-aspartate receptors. J Pharmacol Exp Ther 1992;260:1209-1213. 12. Slogoff S, Allen GW, Wessels JV, Cheney DH. Clinical experience with subanesthetic ketamine. Anesth Analg 1974;53:354-358. 13. Akamatsu TJ. Experiences with the use of ketamine for parturition. I. Primary anesthetic for vaginal delivery. Anesth Analg 1974;53:284. 14. Sadove MS, Shulman M, Hatano S, Fevold N. Analgesic effects of ketamine. Anesth Analg 1971; 50:452-457. 15. Apfelbaum JL, Kallar SK, Werchler BV. Adult and geriatric patients. In: Wetchler BV, ed. Anesthesia for ambulatory surgery. Philadelphia: JB Lippincott, 1991:197-307. 16. Oshima E, Tei K, Kayazawa H, Urabe N. Continuous subcutaneous injection of ketamine for cancer pain. Can J Anaesth 1990;37:385-392. 17. Roytblat L, Korotkoruchko A, Katz J, Glazer M, Greenberg L, Fisher A. Postoperative pain: the effect of low-dose ketamine in addition to general anesthesia. Anesth Analg 1993;77:1161-1165. 18. Tiseo PJ, Inturrisi CE. Attenuation and reversal of morphine tolerance by the competitive n-methyld-aspartate receptor antagonist LY274614. J Pharmacol Exp Ther 1993;264:1090-1096.
Vol. 10 No. 4 May 1995
Palliative Care Rounds
Effective Treatment of Severe Cancer Pain of the Head Using Low-Dose Ketamine in an Opioid-Tolerant Patient J o h n L. Clark, MD, a n d Gary. E. Kalan, MD Department of Anesthesiolo~, Greenwich Hospital, Greenwich, Connecticut
Abstract We report the ~z~se of a 39-year-oM man with severe pain due to unresectable squamous-cell carcinoma of the maxillary,' sinus that had invaded cranial bone and had metastasized to the cervical spine. Tolerance to opioids had developed, and high doses of transde~vnal, continuous intravenous, and epidural opioids did not control his pain. An acute episode of extremely severe head pain was immediately controlled with a subanesthetic dose of ketamine after failure of a stress dose of corticosteroid and intravenous lidocaine. Because the patient was terminally ill and invasive procedures were not options, we controlled his pain using a low-dose ketamine infusion until his death 13 dm, s later. Ketamine may be a good co-analgesic/or breakthwugh pain and for severe pain caused by terminal cancer when invasive techniques are inappropriate. Its mechanism of action may include reversal of opioid tolerance in addition to an inherent analgesic effect. J Pain Symptom Manage 1995;10:310-314.
Key Words Cancer pain, breakthrough pain, pain management, ketamine, opioid, tolerance, N-methylD-aspartate receptor
Patients with severe cancer pain may be very difficult to manage. In the terminal stage of disease, radiotherapy, surgery, and c h e m o t h e r apy will no longer be effective, and patients may b e c o m e tolerant to potent opioids. If intravenous infusion of opioids or intraspinal administration of opioids, with or without adjuvant drugs, do not control the pain, neuroablative procedures may be necessary.t Neuroablative procedures may be a p p r o p r i a t e in
Address reprint requests to:John L. Clark, MD, Greenwich AnesthesioloD, Associates PC, PO Box 772, Greenwich, CT 06836, USA. Acceptedfor publication: September 22, 1994. © U.S. Cancer Pain Relief C;ommittee, 1995 Published by Elsevier, New York, New York
major medical centers; they may not be available in c o m m u n i t y hospitals. We r e p o r t a case of a patient with terminal cancer of the maxillary sinus who e x p e r i e n c e d extremely severe acute pain while being treated with high doses of transdermal, continuous intravenous, and continuous intraspinal opioids. At the m o m e n t of crisis, a subanesthetic dose of ketamine was administered empirically, and the patient e x p e r i e n c e d dramatic relief of pain. Thereafter, we were able to manage his pain pharmacologically with low-dose ketamine and opioids. We speculate that ketamine was effective because it is analgesic in low doses and because it may have reversed opioid tolerance in our patient. We r e c o m m e n d that 0885-3924/95/$9.50 SSDI 0885-3924(95)00010-V
VoL 10 No. 4 May 1995
Ketamine ]br Severe Cancer Pain
ketamine be considered as an adjuvant drug in certain patients with severe cancer pain.
Case Report A 39-year-old man developed pain due to recurrent squamous-cell carcinoma of the maxillary sinus that was resistant to chemotherapy and radiation therapy. Fifteen months prior to admission, carcinoma of the left maxillary sinus was diagnosed, and he underwent left maxillectomy, anterior and posterior ethmoidectomy, and radiation therapy. T h e r e was no evidence of invasive disease. Nine months prior to admission, the patient complained of sinus pain, and r e c u r r e n t tumor destroying the lacrimal bone was diagnosed. The patient underwent craniofacial resection. Subsequent chronic pain of the left face and orbit was treated with trigeminal nerve block. These procedures were carried out at a major medical center. Four months prior to admission, recurrent tumor was again diagnosed. Surgery was no longer possible, and the patient was treated with high-dose chemotherapy using cis-platin u m and 5-fluorouracil. The tumor progressed to involve the left orbit and metastasized to the body of C2. T h e patient was treated at h o m e with intravenous nutrition, transdermal fentanyl, and subcutaneous levorphanol until he was admitted to our hospital because of weakness and a change in mental status secondary to hypercalcemia. Intravenous fluid and pamidromate therapy reversed the hypercalcemia, and his mental function returned to normal. He complained of neck and facial pain. Cervical spine radiographs showed destruction of the C2 vertebral body. His neck was stabilized with a collar. The left side of his face was distorted from swelling due to inflammation and tumor growth, and he wore a patch over his left orbit. The goal of therapy was to control his pain so that he could return home. On admission, his pain was managed with transdermal fentanyl totalling 400 p g / h r and levorphanol 2-4 mg subcutaneously every 2 hr. He refused radiation therapy as a m e t h o d of pain control. During the first week his face and neck pain worsened rapidly, and his opioid requirement increased to fentanyl 1600 p g / h r transdermally and levorphanol 12 mg subcutaneously ever}, 2
311
hr. Dexamethasone, 4 mg intravenously (IV) every 8 hr, briefly reduced his pain. The anesthesia service was consulted after his second week o f hospitalization because his pain was not controlled with fentanyl 1600 g g / hr, levorphanol infusion 30 m g / h r plus 15-rag bolus doses for breakthrough pain, and supplemental lorazepam 1 mg intravenously every 4 hr for anxiety. Initial consideration was given to converting the patient to a continuous intravenous fentanyl infhsion, but this was not possible due to the high doses required by the patient and a limited supply of fentanyl. An epidural catheter was inserted to increase cerebrospinal fluid levels of opioid by the intraspinal route. A 5 mg bolus of epidural m o r p h i n e was given followed by a continuous epidural m o r p h i n e infusion at 0.4 rag/hr. Levorphanol was increased to 40 m g / h r IV. His level of pain decreased slightly over the next 24 hr, then worsened. During the second day of epidural m o r p h i n e therapy, the levorphanol infusion was replaced with a continuous m o r p h i n e infusion that was titrated up to 120 m g / h r and supplemented with 10-15 nag boluses for breakthrough pain. Transdermal fentanyl was continued at 1600 p g / h r , and anxiety was treated with midazolam 1-2 mg IV as needed. During the third day of epidural m o r p h i n e therapy, his pain worsened, and the infusion rate was increased to 0.8 m g / h r , then to 1 r a g / hr. T h e patient acutely developed a severe headache. The intravenous m o r p h i n e infusion was increased to 240 m g / h r , supplemented with 30 mg IV boluses. An intracranial hemorrhage was suspected, and the patient was given mannitol 1.5% 50 cc IV and dexamethasone 100 mg IV for increased intracranial pressure. This was not effective. T h e patient clutched his head and started screaming. The oncologist requested an urgent anesthesia consultation for pain control. Lidocaine 100 mg IV was first administered but had no beneficial effect. Next a subanesthetic dose of ketamine, 50 mg IV, was given, which promptly relieved his pain. T h e patient relaxed, stopped clutching his head, and smiled. After 30 min, his head pain returned. The patient was alert e n o u g h to say the effect of the drug was acceptable and asked that it be given again. Ketamine 25 mg IV and 100 mg ketamine intramuscularly (IM) were
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given for pain control until an infusion could be prepared. A rate of 100 m g / h r was chosen for analgesia because the first dose of 50 mg had an effect lasting about 30 min. During the first 24 hr, treatment for b r e a k t h r o u g h pain was required only once. On the second day of ketamine infusion therapy, the epidural catheter was removed. On the third day of therapy, the transdermal fentanyl was discontinued while the IV infusion of m o r p h i n e was continued at 330 m g / h r . T h e patient r e m a i n e d comfortable, and no additional m o r p h i n e was required for b r e a k t h r o u g h pain. He was able to sleep at night. Although sedated, his wife was able to speak to him at times, and he recognized his b r o t h e r who had traveled f r o m J a p a n to be with him. T h e patient ultimately developed p n e u m o nia. A c e t a m i n o p h e n was used to reduce fever. However, the patient a p p e a r e d agitated to his family and nurses. T h e r e was concern that he was again suffering pain, and the oncologist o r d e r e d increases in the drug-infusion rates. Doses of m o r p h i n e 1000 m g / h r , midazolam 12 m g / h r , and ketamine 200 m g / h r were reached before the patient expired on day 13 of continuous ketamine infusion.
D/seuss/on O u r patient e x p e r i e n c e d moderate-to-severe pain, a c o m m o n experience r e p o r t e d by 6 0 % 90% of patients with advanced cancer.l Most of these patients can be m a n a g e d with pharmacologic therapy using the World Health Organization (WHO) three-step "analgesic ladder," which progresses from n o n o p i o i d analgesic therapy to " s t r o n g " opioid therapy with or without adjuvant drugs. 2':~ The W H O recomm e n d s m o r p h i n e as the drug of choice for severe cancer pain because of its frequent use and wide availability. The W H O regimen has been validated by Ventafridda and associates in a retrospective study of patients with advanced or terminal cancer. 3 Pharmacologic therapy may fail to control severe cancer pain. O u r patient fits into a category of patients described by Coyle and colleagues, whose pain could not be relieved despite changing opioids, combining opioids, using high doses of opioids, and administering these drugs by all available routes. 4 A n o t h e r
Vol. 10 No. 4 May 1995
p r o b l e m was that we could not evaluate the exact etiology of o u r patient's pain at the time of crisis. T u m o r s of the paranasal sinuses are known to cause severe pain because of direct invasion of the base of the skull and t u m o r involvement of nerves. 1 O u r patient may have e x p e r i e n c e d lancinating pain in the distribution of the trigeminal nerve. In a major medical center, neurosurgical ablative techniques, neurolytic gasserian ganglion block, and intraventricular opioids might have b e e n options, but we were limited to a pharmacologic approach in an acute situation without an exact diagnosis. T h e initial a t t e m p t to achieve analgesia with a bolus dose of lidocaine was based u p o n reports that this had b e e n effective in the relief of both vascular headaches and central pain syndromes. ~'6 The p r o p o s e d mechanisms include local inhibition of nociceptive trigeminal afferents that innervate cranial blood vessels and a central effect that decreases spontaneous burst activity of abnormally active neurons. Ketamine hydrochloride was chosen empirically because it is a general anesthetic that is effective in subanesthetic doses with a very low risk of respiratory depression. It is an arylcycloalkylamine similar to phencyclidine hydrochloride (PCP) and is used to create a state of "dissociative anesthesia." While receiving this drug, the patient may cry out and move in response to a painful stimulus but has no awareness of the pain. 7,s Ketamine is most effective as an anesthetic for somatic pain; it is not as effective against visceral pain. A benzodiazepine is usually given along with ketamine to prevent unpleasant psychic disturbances, such as unpleasant dreams, delirium, and hallucinations. 7 Like m o r p h i n e , ketamine is an inexpensive, widely available drug that has b e e n used for analgesia and anesthesia u n d e r adverse conditions, including mass casualties during wartime and in developing countries where trained anesthetists are not available. 9 It is supplied as a racemic mixture of two optical isomers, chiral forms (S)ketamine and (R)-ketamine, in 1%, 5%, and 10% solutions. Ketamine's m e c h a n i s m of action has not been fully explained. Recent studies 1°'11 suggest that its analgesic and anesthetic actions are explained by blockade of the N-methyl-D-aspar-
Vol. 10 No. 4 Mm, 1995
Ketamine for Severe Cancer Pair~
tate (NMDA) receptor. The NMDA receptor is one type of receptor for excitatory amino acids, such as L-glutamate and L-aspartate, which may be important in nociceptive sensor?" transmission. 1° In a study by Oye and coworkers, the chiral forms of ketamine were used as probes for NMDA receptor-mediated neurotransmission. 1~ (S)-ketamine was four times as potent as (R)-ketamine in reducing pain perception and in causing auditory and visual disturbances, and both caused dissociative disturbances in the form of feelings of d e t a c h m e n t from the body. Both forms of ketamine displaced a non-competitive NMDA receptor antagonist (MK801) from specific binding sites in membrane fractions of brain homogenates. These findings indicated that inhibition of sensor}; perception by subanesthetic doses of ketamine is due to PCP site-mediated noncompetitive blockade of NMDA receptor operated channels. For induction of general anesthesia in the adult, ketamine is administered in an intravenous dose of 1-3 m g / k g over 1 min or in a dose of 6.5-13 m g / k g IM. s Because of its psychic effects, it is rarely used in anesthetic doses. Instead, it is used in subanesthetic doses to provide analgesia for a variety of purposes. Slogoff and coworkers r e c o m m e n d e d a dose of 1.5 m g / k g IM to provide 15 min of analgesia for burn dressing changes, 1~ and Akamatsu recomm e n d e d 0.2-0.4 m g / k g IV to provide safe, brief analgesia for vaginal delivery', l~ Sadove and colleagues found that ketamine 0.44 m g / kg IM provided effective analgesia for postoperative pain lasting up to 60 rain with most patients experiencing only dizziness and pleasant psychic effects. 14 InflLsion of midazolam 0.05-0.15 m g / k g IV followed by low-dose ketamine 0.25-0.5 m g / k g 1V provides safe intravenous conscious sedation without respiratoo' depression during outpatient cosmetic surgery u n d e r local anesthesia. 1"~' Oshima and associates reported that continuous low-dose subcutaneous ketamine at 2.5-15 m g / h r was effective in providing analgesia in 13 of 18 terminal cancer patients who were refractor)' to opioids. 16 A recent study by Roytblat and colleagues examined the effect of low-dose ketamine in addition to general anesthesia on postoperative pain. 17 They gave patients in the study group ketamine 0.15 m g / k g IV 5 rain before
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surgical incision and observed a reduced dose r e q u i r e m e n t for m o r p h i n e in the first 24 hr postoperatively. They suggested that ta-opioid agonists such as m o r p h i n e and fentanyl act synergistically with the NMDA receptor antagonist ketamine hydrochloride. Our patient received ketamine 50 mg IV initially, or 0.92 m g / k g based on his weight of 54.5 kg. This is a high dose when compared to the doses used in the above reports, but our patient never became anesthetized, and we were able to speak with him during the period when his pain was relieved. On the basis of this clinical experience, lowdose ketamine therapy appears to be safe. This drug is an anesthetic, however, and has the potential for loss of consciousness, airway obstruction, and respiratory depression. Therefore, ketamine therapy should be titrated, starting with very small doses, such as 5-10 mg by IV bolus or 0.1-0.2 m g / k g / h r by infusion. Equipment for airway m a n a g e m e n t should be readily available. Recent work by Tiseo and Inturrisi using laboratory animals indicates that N-methyl-D-aspartate receptor antagonists can attenuate and reverse m o r p h i n e tolerance, is A noncompetitive NMDA antagonist MKS01 and a competitive antagonist LY274614 were studied. Both agents significantly attenuated the development of m o r p h i n e tolerance when given simultaneously with morphine. Treated animals seemed to maintain their sensitivity to morphine for 1 week after therapy was stopped in contrast with the control animals, and LY274614 restored m o r p h i n e sensitivity in tolerant animals. Because MK801 and other noncompetitive NMDA antagonists produce PCPlike behavior in animals, these authors r e c o m m e n d that competitive NMDA antagonists, such as LY274614, be developed as adjuncts for patients receiving chronic opioids for pain m a n a g e m e n t because they lack phencyclidine-like side effects. Ketamine is a noncompetitive NMDA antagonist, which may have reversed opioid tolerance in our patient. The dramatic pain relief after a subanesthetic dose of ketamine may be explained, therefore, by the analgesic effects of low-dose ketamine, the synergism of ketamine and morphine, and the reversal of tolerance, which could have allowed our patient to experience the full analgesic and euphoric effects of
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o p i o i d therapy. Until a m o r e specific N M D A r e c e p t o r antagonist b e c o m e s available, we believe that k e t a m i n e may be used in subanesthetic doses as an a d j u n c t or coanalgesic in opioid tolerant patients e x p e r i e n c i n g severe c a n c e r pain.
R•• 1. Bonica JJ. The management of pain. Philadelphia: Lea and Febiger, 1990:400--460, 804-809. 2. World Health Organization (WHO). Cancer pain relief. Geneva: WHO, 1986:19. 3. Ventafridda V, Tamburini M, Caraceni A, De Conno F, Naldi F. A validation study of the WHO method of cancer pain relief. Cancer 1987;59:850856. 4. Coyle N, Adelhardt J, Foley KM, Portenoy RK. Character of terminal illness in the advanced cancer patient: pain and other symptoms during the last four weeks of life. J Pain Symptom Manage 1990;5: 83-93. 5. Maciewicz R, Chung RY, Strassman A, Hochberg F, Moskowitz M. Relief of vascular headache with intravenous lidocaine: clinical observations and a proposed mechanism. Clin J Pain 1988;4:11-16. 6. Backonja M, Gombar K. Response of central pain syndromes to intravenous lidocaine.J Pain Symptom Manage 1992;7:172-178. 7. Jaffe JH. Drug addiction and drug abuse. In: Goodman AG, Rall TW, Nies AS, Taylor P, eds. Goodman and Gilman's the pharmacologic basis of therapeutics. New York: Pergamon, 1990:557-558. 8. Marshall BE, Longnecker DE. General anesthetics. In: Goodman AG, Rall TW, Nies AS, Taylor P, eds. Goodman and Gilman's the pharmacologic ba-
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sis of therapeutics. New York: Pergamon, 1990:306307, 9. Atkinson RS, Rushman GB, Lee JA. A synopsis of anesthesia. Bristol: IOP, 1987:247-250. 10. Yamamura T, Harada K, Okamura A, Kemmotsu O. Is the site of action of ketamine anesthesia the N-methyl-D-aspartate receptor? Anesthesiology 1990; 72:704-710. 11. Oye I, Pausel O, Maurset A. Effects of ketamine on sensory perception: evidence for a role of n-methyl-d-aspartate receptors. J Pharmacol Exp Ther 1992;260:1209-1213. 12. Slogoff S, Allen GW, Wessels JV, Cheney DH. Clinical experience with subanesthetic ketamine. Anesth Analg 1974;53:354-358. 13. Akamatsu TJ. Experiences with the use of ketamine for parturition. I. Primary anesthetic for vaginal delivery. Anesth Analg 1974;53:284. 14. Sadove MS, Shulman M, Hatano S, Fevold N. Analgesic effects of ketamine. Anesth Analg 1971; 50:452-457. 15. Apfelbaum JL, Kallar SK, Werchler BV. Adult and geriatric patients. In: Wetchler BV, ed. Anesthesia for ambulatory surgery. Philadelphia: JB Lippincott, 1991:197-307. 16. Oshima E, Tei K, Kayazawa H, Urabe N. Continuous subcutaneous injection of ketamine for cancer pain. Can J Anaesth 1990;37:385-392. 17. Roytblat L, Korotkoruchko A, Katz J, Glazer M, Greenberg L, Fisher A. Postoperative pain: the effect of low-dose ketamine in addition to general anesthesia. Anesth Analg 1993;77:1161-1165. 18. Tiseo PJ, Inturrisi CE. Attenuation and reversal of morphine tolerance by the competitive n-methyld-aspartate receptor antagonist LY274614. J Pharmacol Exp Ther 1993;264:1090-1096.