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Long-term ketamine subcutaneous continuous infusion in neuropathic cancer pain
Long-Term Ketamine Subcutaneous Continuous Infusion in Neuropathic Cancer Pain Sebmiano Mercadantc, MD, Franc0 Lodi, MD. Monica Marina Calligara, MD, and Roberto Serretn, MD Tt n/AW a(rkar/m(r(ti. hkma; fkpwtmar o/ T&&w
Cancer pain that is inferred to have neure pathic mechanism can be clinically challcnging. Although pin mechanism should not be used as a criterion to determiuc opioid responsivencsi,” and ncuropathic pain does
AU&U r$wint rqu”tj to. Dr..%-ba*tiano Prin Wclicl and Palli.ctiw <‘;rrc, SXS407: 191, 90125. Pakrnw. ItAv.
publirtiion:
MD,
aud Iatn-uiue Gnv (.S M.. MS.. KS. A Bucchni La Fkia Hflspikrl Pain ILIL/ and Pdlia~i~u Cm Lb13 (SM.). .SAMOI: Pahmo; and (EL, MC.), Fomuic Efrdiciw, L’nivmity oj Milan. Man. II&
lnhpducrion
Arc+ei/or
CGo.
January
13.
1995.
Mcrtadantr, \1a Libcrti
not show any particular disadvantage in the overall prognosis of the pain.’ som:* patients with neuropathic pain arc extremely dificult to manage.’ Ketamiuc. au N-methyl-D-aspartate (NMDA)-rcccptor noncompetitive antagonist, may be ap alternative kolution for the treatment of ncuropathic :,ain unresponsive LO opioid escalation. Ketalnine has been recognized for many yean as an anesthetic.” Sub anesthetic doses can yield analgesia without hypnosis.” Recent reports have described pr+
longed analgesic effects from kecamine in patients with neuropathic pG5*‘*’ We now report the first case in which a long-term sub cutaneous infusion of lcetamine was used in the home setting to manage advanced cancer pain that was not responsive lo’ eirher oral morphine or combined morphine-bupivacaine spinal infusion.
A 67yearold man preselrred with a 3-mont.h history of bilateral lumbosacrat pain. The pain interfered with his steep and was described as tancinating, burning, shooting, or aching ir, character. On physirat examination, there was weakness in the right leg, and decreasc
phine 80 mg and bupivacainel5 mg a day were started continuously. A supplemental bobs de of 1 mg of bupivacaine and 5.3 mg of morphine was also offered “as needed.” Oral morphine was reduced to 2 g a day according lo a schedule already used for oral-spinal conversion,’ and he was discharged home. The patient did not tolerate this treatment He described an excruciating sensation (like “a vice in the legs”) and myoctonus. without reporting any advantage in terms of pain relief. He rcfuscd co continue the mtment preferring the previous unfavorable treatment wilh oral opioids. The catheler was removed and oral morphine was again increased to 5 g daily. The pain was not welt controlled. The patient was not able 10 walk or eat because of pain and the periods of confusion and haltucinations lengthened. Episodes of vomiting appeared. His daughter, a general practitioner, was in a hopeless state, exhausted by her father’s poor quality of life. A subcutaneous “buuedy” cannula was placed in the anterior thoracic wJI, and a continuous subcutaneous infusion of ketamine 150 mg a day (2 mg/kg) was given using a portable syringe driver. Excellent pain relief was rapidly achieved, permitting the lpaduat reduction of the morphine dose to 200 mg daily over the next 2 weeks. The neurological side effects dramatlzdty decreased. Haloperidol5 mg a day was mixed with ketamine in the same syringe, yielding good conuot of vomiting. A sensation of nausea remained. The patient was able to walk, ahhough wilh some difficulty due to right leg weakness. and began eating again. Karnobky performance status score was 50-60. The patient continued this trcaunent for 2 months achieving acceptable pain relief Throughout this paiod. HC then required an increase in kctamine dosage lo 200 mg/day (about IO mg/hr). Only rare. minor, self-limited episodes of neurological impairment, including confusion and drowsiness, were evidenced. After 3 moultis, fhe pain relief continued to. be acceplabte. The patient was receiving sub cutaneous keramine 200 mg daily mixed with hatoperjdol5 mg daily, oral morphine 200 mg daily, and oral prcdnisone 50 mg daily. Ketamine was temporarily disconGnucd due to inadequate avGlability, and the symptomaloc ogy worsened.
EZq KE-
0wh.U MOdoumg MOroult -
200
at. 240
240
!I00
S.C.
396
!32r
200
!Joo
150(450)
0.L 66
O.S. 36
XC.
105
MOamccnttation
(n $-) ml@
Morphine and Letamine plasma concenttion during 5 months of therapy are shown in Table 1. These values were obtained using a gas chromatography qcthod (HP 5890, series II), with mass spect.romeuy (HP 5972) for ketamine and radioimmunoassay (Coat-a count serum morphine, DPC. Los Angeles) for mor-
phine. When a large neck mu,
developed. pain he1 worsened. Oral morphine dosage was increased to so0 mg daily, and ketamine was increased to 246 mg daily (Table 1 j. Drowsineti and conftuion appeared again. laboratory Enc!ings showed a plasma creatininc concentration of 2.7 mg96. The patient’s oral intake declined due to dysphagia, and Karnofsky performance status score wds 40. Morphine was administered as a continuous subcutaneous infusion (159 mg dailv), and the kctamine dosage was increased to SO0 mg daily (Table 1). The patient agreed to radiotherapy to the ueck mass but it was suspended due to the app-.qrancc of intolerable side effects (vomiting). The oosages of morphine ar?d kctamine were progressively incrcd to 200 mg and 450 mg daily. respectively, which again provided acceptable pain relief until the patient’s death. The total duration of ketamine tJwrdpy was 13 months. The progressive neurological impairment observed in the last stage of illness was attributed to progression of discasc: and the limited intakt of food and fluids, tether than to the effects of the drugs administcted.
Spinal NMDA receptors play a role in nociceptive processing. ‘e Several experimental studies have shown that repetitive C-Wer acti~tion produces centtal changes that may be relevant to neuropethic pain and are attenuated by NMDA receptor antagonists.’ ‘-‘s These experimental observations suggest that ketamine and other NMDA antagonists may be use.-~l in neuropatl.ic cancer pain. Ketamine has many proper! ICSthat may be aclvantageous in advanced cancer patients. inclu Jing rapid onset of effect and low incidence 01’ rcspitatory depression. Hohwer, so-caIled etnergence ,reactions. excessive salivation, and pr& longed recovery time limit its routine use. Side effects of excess salivation, purposeless movements, and behavior changes have beets reported after both inttavcnously and intnr muscular use.” Administration of subdissociativt doses of kttamine provide balanced sedation with lintited respiratory depression, emergence phcnomena, and significant changes in hlood pressure or heart rate.G The dosage that leads to side effects is not clear, especially in adv;rnccd cancer patients, who are often predisposed to confusion and delirium due to tumor effects, metabolic disturbances, or the use of other drugs. The daily dose of kcumine initially used in our patient was very low compared to previous experience in chronic pain and cancer pain patients (ranging from 0.2 mg/kg/hr to I.5 mg/kg/hr).s*‘“*‘. In a previous report. I3 of 18 patients achieved good pain relief with infusion rates of 60-560 mg/day (2-15 mg/hr).‘!’ Seven1 routes of administration were used by Luczak et al. (cited in Twy cross”), mostly to relieve pain on rtovement (e.g., turning and washing bedridden patients) in 26 canctr patients with different pain syndromes (dosage ranging from 40 to lE!O mg/day). Some patieuts described in these reports received ketaminc for 4-6 months. In other experiences with ketamine in neuropathic cancer pain, the dosage could be reduced during the course of the therapy without a return of pain.‘” Our patient was administered ketamine for over I year. Although a placebo effect might be considered, the duration of good effect in
a cancer patient unresponsive to opioids makes this possibility unlikely. The dose of ketaminewasgtaduaKyincreasedto4!5Omga day. Although tolerance and enzyme induction have been reported following chronic administration, the slow escalation seems more attributable to an increase of the pain from the progression of the cancer than the appeatance of ketamine tolerance. Although the side effects of ketamine often outweight the benefits, in this patient the neurob& symptoms were attributable to the previous high opioid dosage and were reduced after starting ketamine. Important adverse effects, such as injection site inflammation, salivation, and insomnia, were not observed in spite of the long period of administration and the dosage used in time. The ketamine blood concentration was related to dose increases during the treatment Norketamine, an active metabolite with ottothird the potency of ketamine, can account for part of the analgesic efTect observed with a constant infusion. The influence of this metabolite possibly reduced the need for higher opioid and ketamine doses. Norketamine concentrations are higher following oral administration than parenteral administration, probably from first-pass merabolism.‘” Ketamine metatolites were not determined in this case. Free morphine blond concentration decreased while total morphine blood concentration (including morphine-6glucuronide and morphineSglucuronide) irrcreased when the dosage of oral morphine was increased from 200 mg up to 300 mg after about 7 weeks. The free morphine/total morphine ratio changed (about l/20) when morphine 150 mg was continuously administered by su& cutaneous route. The response in this case suggests that ketamine may have a positive effect on opioid responsiveness, reversing a rightward shift of the dose-response curve that may be typical of some pain syndromes. Ketamine infusion may represent an alternative pharmacological method to control ncuropathic cancer pain. The influence of kctamine on opioid analgesia could also result from a reversal of opioid tolerance. Mu-opioid tolerance involves the mediation of NMDA reccpton and the nitric oxide system.” Muapioid-NMDA rcccp toy interaction results in‘an increase of intra-
cellular free calcium.yP NMDA receptor protagonists would be expected to inhibit tolerance to the analgesic effect of repeated morphine administration, interfering with the ccllular and molecular changes thought to be involwd in pain tolerance mechanisrwPg-15 Regardiug the myoclonus induced by spinal morphine, this effect is well recognized, although the mechanism is not clear. it was refractory to local anesthetic addition at the concentration used in this patient This observation has been already reported with other opioids.” We found that a low-dose continuous subcutaneous infusion of ketamine was reliable and well accepted. By changing the skin site every 2 days. we did not observe adverse reactions at the subcutaneous site. The use of continuous subcutaneous ketamine may be useful in neuropathic cancer pain unresponsive to opioiclr. Other studies should be performed to confirm the role and the optimal dwgc of this drug in cancer pain.
Ackmwledgmed I wish to thank Dr. Robert Twycross for the materials kindly supplied and Prof. Geoffrey W. Hanks for his comment. We would like to thank Mrs. Josephine Muscat for her help in translating the manuscript.
w
e?x?nces
I. McQuay IIJ. Jadad AR, Carroll D. et al. Opioic! sensitivity of chronic pairl: a paticntcontrolled anal-
gesia method. Anesthesia 199!2;47:757-767. 2. Portenoy RR, Foley KM, fnturrisi CE. The nature c+‘opioid responsivcn= and its impbcations for neuropathic pain: new hypotheses deriwd from studies of opioid infusion. Pain 199@43:23S-286.
3. Merradante S, Maddaloni S, Roccclla S, Salqgio I.. Predictiw factors in advanced cancer pain treated only by analgesicr.,Pain 1992:5Oz151-155. 4. Brucra
E. MacMillian
RN. The Fllmonton preliminary
report.
R, Hanson J. MacDonald for cancer pain: Pam 198Y;S7:293-269. 51aging'sptem
5. !Sosnow)ri M. Loss&al D. Fodder& L. Revem ibility of opioid insensitive pain. Seventh World Congress on Pain in Paris. August 22-27, i993:16. 6. Slogoff S, Allen CW, Vessels LV. Cheney Dti. Clinical exprriencc with subanacsthetic lutaminc. Anesth Analg 1974;55:354-358. 7. Backonja Zimmermann
M, Amdt G, Gombar KA. Check B. M. Response of chronic neumpathic
pain gadtomes to kttaminc: a preliminary study. Pain l9%5&51-57. 8. Oye I. Mathisen L. Skjelbred P. Studies on effea of ketaminc a&gesia In neuropathic pain. !3tg~;~~~~~~~gress on Pain in Paris: August : . - . 9. Mexadante S. Intratbccal morphine and bupivacaine inadvanced cancer pain patients imp!antcd at home, J Pain Symptom Manage 1994+201-207. 10. codcrre TJ. Katz J. Yaccarino AL, Meback R. Contribution of cenval ncufoplasticity to path&y en: ~S~;fcu~ and experimental cvi;: L. Il. Dickensan AH, Sullivan AF. Differential effects of excitatory amino acid antagonist on dorsal horn nocicept&e neurons in the mt. Brain Rcs 19905006: 31-59. 14. White PF. Clinical uses of intravenous ones ~bctic and analgesic infusions. Ancsth Analg I* 8:371-177.
13. Yamamoto +I’,Yabh TL Comparison of the antinociceptive cffccts of the pre and post treatment with intrathccal morphine and MK801. an N?fDA antagonist on the formalin test in the rat. Anesthesiology 1992;77:757-X3. 14. Malbcrg AB, Yak& TL Spinal nitric oxide synthesis inhibition Mocks NMDA-induced thermal hypcralgcsia and produces antinociception in the formdin test in rats. Pam 1999~291-300. 15. Damr G, Hama A. Dcykin A. Vos B. Maciewicz R MK801 blocks the development of thermal induced hyperalgesia in a ran model of cxprimcntal painful neuropathy. Brain Res 1991:353:327so. 16. Mao J. Price DD, M;rycr DJ. 1.u J, Hayes RL. lntn~l:cc~l MK8Ul and Iucal nerve ancsthcua synrrgistically rcdrwc nuciccprive behaviors in rats with txprrimcnral pcriphctal mononcuropathy. Brain Rcs 1992;576:254-262.
17. Reich DL, Sihay C. Kctaminez an upd.~te on the fitst twenty&e years of clinical experience. Can J Anaesth 1989$6:186-197. 18. Twycross R. Pain relief in advanad cancer. Oxford. 1994~476-479. 19. Oshima E. Continuous subcutaneous injectitin of ktamine for cancer pain. Can J Anaesth 1990; 37:383-392. 20. Grant IS, Nimmo WS. McNicol LR Clements JA. Kctamine disposition in children and adults. Br J Anestl 1981;53:27-SO. 21. Elliot 1c Minami N, Koksnikov VA, Patemalt GW, lnturrisi CE. The NMDA receptor antagonists, LY2746!1 and MKSOI. and the nitric oxide synthasc inhibitor, NGnitrownine. attenuate analgcsic tolerance to the muopioid morphine but not to kappa opioids. Pain 19945689-75. 22. Mayer L, Miller RJ. Excitatory amino acid receptors, second messengers and regulation of intracellular Ca++ in mammalian neurons. In: Lodge D. CoIlingridge G, eds. The pharmacology of excitatory amino acids, Cambridge: Ehcv+crTrends, 199o:!t6-42. 29. Marck P, &n-Eliyahu S, Gold M. lebcskind JC. Excitatory amino acid antagonists (kynurenic acid and MK801) attenuirte the development of morphine tolerance in rat Brain Rcs 1991;547:177-181. 24. Trujillo KA. Akil H. Inhibition of morphine tolerance utd dependence by the NMDA receptor antagonist MK 801. Science 1991;51:85-87. 25. Foley KM. Changing concepts of tolerance IO opioids: what the cancer patient taught us. IASP Refresher Course Syllabus, Seventh World c011gms.s on Pain iu Paris; August 22-27, 1993:22l-255. ‘26. Cartwright PD, Ilcsa C. Jacksou AO. Myoclonur spasms following intnthecal diamorphine. J Pain Sympunn Manage 1993;8:492-495.
Cancer pain that is inferred to have neure pathic mechanism can be clinically challcnging. Although pin mechanism should not be used as a criterion to determiuc opioid responsivencsi,” and ncuropathic pain does
AU&U r$wint rqu”tj to. Dr..%-ba*tiano Prin Wclicl and Palli.ctiw <‘;rrc, SXS407: 191, 90125. Pakrnw. ItAv.
publirtiion:
MD,
aud Iatn-uiue Gnv (.S M.. MS.. KS. A Bucchni La Fkia Hflspikrl Pain ILIL/ and Pdlia~i~u Cm Lb13 (SM.). .SAMOI: Pahmo; and (EL, MC.), Fomuic Efrdiciw, L’nivmity oj Milan. Man. II&
lnhpducrion
Arc+ei/or
CGo.
January
13.
1995.
Mcrtadantr, \1a Libcrti
not show any particular disadvantage in the overall prognosis of the pain.’ som:* patients with neuropathic pain arc extremely dificult to manage.’ Ketamiuc. au N-methyl-D-aspartate (NMDA)-rcccptor noncompetitive antagonist, may be ap alternative kolution for the treatment of ncuropathic :,ain unresponsive LO opioid escalation. Ketalnine has been recognized for many yean as an anesthetic.” Sub anesthetic doses can yield analgesia without hypnosis.” Recent reports have described pr+
longed analgesic effects from kecamine in patients with neuropathic pG5*‘*’ We now report the first case in which a long-term sub cutaneous infusion of lcetamine was used in the home setting to manage advanced cancer pain that was not responsive lo’ eirher oral morphine or combined morphine-bupivacaine spinal infusion.
A 67yearold man preselrred with a 3-mont.h history of bilateral lumbosacrat pain. The pain interfered with his steep and was described as tancinating, burning, shooting, or aching ir, character. On physirat examination, there was weakness in the right leg, and decreasc
phine 80 mg and bupivacainel5 mg a day were started continuously. A supplemental bobs de of 1 mg of bupivacaine and 5.3 mg of morphine was also offered “as needed.” Oral morphine was reduced to 2 g a day according lo a schedule already used for oral-spinal conversion,’ and he was discharged home. The patient did not tolerate this treatment He described an excruciating sensation (like “a vice in the legs”) and myoctonus. without reporting any advantage in terms of pain relief. He rcfuscd co continue the mtment preferring the previous unfavorable treatment wilh oral opioids. The catheler was removed and oral morphine was again increased to 5 g daily. The pain was not welt controlled. The patient was not able 10 walk or eat because of pain and the periods of confusion and haltucinations lengthened. Episodes of vomiting appeared. His daughter, a general practitioner, was in a hopeless state, exhausted by her father’s poor quality of life. A subcutaneous “buuedy” cannula was placed in the anterior thoracic wJI, and a continuous subcutaneous infusion of ketamine 150 mg a day (2 mg/kg) was given using a portable syringe driver. Excellent pain relief was rapidly achieved, permitting the lpaduat reduction of the morphine dose to 200 mg daily over the next 2 weeks. The neurological side effects dramatlzdty decreased. Haloperidol5 mg a day was mixed with ketamine in the same syringe, yielding good conuot of vomiting. A sensation of nausea remained. The patient was able to walk, ahhough wilh some difficulty due to right leg weakness. and began eating again. Karnobky performance status score was 50-60. The patient continued this trcaunent for 2 months achieving acceptable pain relief Throughout this paiod. HC then required an increase in kctamine dosage lo 200 mg/day (about IO mg/hr). Only rare. minor, self-limited episodes of neurological impairment, including confusion and drowsiness, were evidenced. After 3 moultis, fhe pain relief continued to. be acceplabte. The patient was receiving sub cutaneous keramine 200 mg daily mixed with hatoperjdol5 mg daily, oral morphine 200 mg daily, and oral prcdnisone 50 mg daily. Ketamine was temporarily disconGnucd due to inadequate avGlability, and the symptomaloc ogy worsened.
EZq KE-
0wh.U MOdoumg MOroult -
200
at. 240
240
!I00
S.C.
396
!32r
200
!Joo
150(450)
0.L 66
O.S. 36
XC.
105
MOamccnttation
(n $-) ml@
Morphine and Letamine plasma concenttion during 5 months of therapy are shown in Table 1. These values were obtained using a gas chromatography qcthod (HP 5890, series II), with mass spect.romeuy (HP 5972) for ketamine and radioimmunoassay (Coat-a count serum morphine, DPC. Los Angeles) for mor-
phine. When a large neck mu,
developed. pain he1 worsened. Oral morphine dosage was increased to so0 mg daily, and ketamine was increased to 246 mg daily (Table 1 j. Drowsineti and conftuion appeared again. laboratory Enc!ings showed a plasma creatininc concentration of 2.7 mg96. The patient’s oral intake declined due to dysphagia, and Karnofsky performance status score wds 40. Morphine was administered as a continuous subcutaneous infusion (159 mg dailv), and the kctamine dosage was increased to SO0 mg daily (Table 1). The patient agreed to radiotherapy to the ueck mass but it was suspended due to the app-.qrancc of intolerable side effects (vomiting). The oosages of morphine ar?d kctamine were progressively incrcd to 200 mg and 450 mg daily. respectively, which again provided acceptable pain relief until the patient’s death. The total duration of ketamine tJwrdpy was 13 months. The progressive neurological impairment observed in the last stage of illness was attributed to progression of discasc: and the limited intakt of food and fluids, tether than to the effects of the drugs administcted.
Spinal NMDA receptors play a role in nociceptive processing. ‘e Several experimental studies have shown that repetitive C-Wer acti~tion produces centtal changes that may be relevant to neuropethic pain and are attenuated by NMDA receptor antagonists.’ ‘-‘s These experimental observations suggest that ketamine and other NMDA antagonists may be use.-~l in neuropatl.ic cancer pain. Ketamine has many proper! ICSthat may be aclvantageous in advanced cancer patients. inclu Jing rapid onset of effect and low incidence 01’ rcspitatory depression. Hohwer, so-caIled etnergence ,reactions. excessive salivation, and pr& longed recovery time limit its routine use. Side effects of excess salivation, purposeless movements, and behavior changes have beets reported after both inttavcnously and intnr muscular use.” Administration of subdissociativt doses of kttamine provide balanced sedation with lintited respiratory depression, emergence phcnomena, and significant changes in hlood pressure or heart rate.G The dosage that leads to side effects is not clear, especially in adv;rnccd cancer patients, who are often predisposed to confusion and delirium due to tumor effects, metabolic disturbances, or the use of other drugs. The daily dose of kcumine initially used in our patient was very low compared to previous experience in chronic pain and cancer pain patients (ranging from 0.2 mg/kg/hr to I.5 mg/kg/hr).s*‘“*‘. In a previous report. I3 of 18 patients achieved good pain relief with infusion rates of 60-560 mg/day (2-15 mg/hr).‘!’ Seven1 routes of administration were used by Luczak et al. (cited in Twy cross”), mostly to relieve pain on rtovement (e.g., turning and washing bedridden patients) in 26 canctr patients with different pain syndromes (dosage ranging from 40 to lE!O mg/day). Some patieuts described in these reports received ketaminc for 4-6 months. In other experiences with ketamine in neuropathic cancer pain, the dosage could be reduced during the course of the therapy without a return of pain.‘” Our patient was administered ketamine for over I year. Although a placebo effect might be considered, the duration of good effect in
a cancer patient unresponsive to opioids makes this possibility unlikely. The dose of ketaminewasgtaduaKyincreasedto4!5Omga day. Although tolerance and enzyme induction have been reported following chronic administration, the slow escalation seems more attributable to an increase of the pain from the progression of the cancer than the appeatance of ketamine tolerance. Although the side effects of ketamine often outweight the benefits, in this patient the neurob& symptoms were attributable to the previous high opioid dosage and were reduced after starting ketamine. Important adverse effects, such as injection site inflammation, salivation, and insomnia, were not observed in spite of the long period of administration and the dosage used in time. The ketamine blood concentration was related to dose increases during the treatment Norketamine, an active metabolite with ottothird the potency of ketamine, can account for part of the analgesic efTect observed with a constant infusion. The influence of this metabolite possibly reduced the need for higher opioid and ketamine doses. Norketamine concentrations are higher following oral administration than parenteral administration, probably from first-pass merabolism.‘” Ketamine metatolites were not determined in this case. Free morphine blond concentration decreased while total morphine blood concentration (including morphine-6glucuronide and morphineSglucuronide) irrcreased when the dosage of oral morphine was increased from 200 mg up to 300 mg after about 7 weeks. The free morphine/total morphine ratio changed (about l/20) when morphine 150 mg was continuously administered by su& cutaneous route. The response in this case suggests that ketamine may have a positive effect on opioid responsiveness, reversing a rightward shift of the dose-response curve that may be typical of some pain syndromes. Ketamine infusion may represent an alternative pharmacological method to control ncuropathic cancer pain. The influence of kctamine on opioid analgesia could also result from a reversal of opioid tolerance. Mu-opioid tolerance involves the mediation of NMDA reccpton and the nitric oxide system.” Muapioid-NMDA rcccp toy interaction results in‘an increase of intra-
cellular free calcium.yP NMDA receptor protagonists would be expected to inhibit tolerance to the analgesic effect of repeated morphine administration, interfering with the ccllular and molecular changes thought to be involwd in pain tolerance mechanisrwPg-15 Regardiug the myoclonus induced by spinal morphine, this effect is well recognized, although the mechanism is not clear. it was refractory to local anesthetic addition at the concentration used in this patient This observation has been already reported with other opioids.” We found that a low-dose continuous subcutaneous infusion of ketamine was reliable and well accepted. By changing the skin site every 2 days. we did not observe adverse reactions at the subcutaneous site. The use of continuous subcutaneous ketamine may be useful in neuropathic cancer pain unresponsive to opioiclr. Other studies should be performed to confirm the role and the optimal dwgc of this drug in cancer pain.
Ackmwledgmed I wish to thank Dr. Robert Twycross for the materials kindly supplied and Prof. Geoffrey W. Hanks for his comment. We would like to thank Mrs. Josephine Muscat for her help in translating the manuscript.
w
e?x?nces
I. McQuay IIJ. Jadad AR, Carroll D. et al. Opioic! sensitivity of chronic pairl: a paticntcontrolled anal-
gesia method. Anesthesia 199!2;47:757-767. 2. Portenoy RR, Foley KM, fnturrisi CE. The nature c+‘opioid responsivcn= and its impbcations for neuropathic pain: new hypotheses deriwd from studies of opioid infusion. Pain 199@43:23S-286.
3. Merradante S, Maddaloni S, Roccclla S, Salqgio I.. Predictiw factors in advanced cancer pain treated only by analgesicr.,Pain 1992:5Oz151-155. 4. Brucra
E. MacMillian
RN. The Fllmonton preliminary
report.
R, Hanson J. MacDonald for cancer pain: Pam 198Y;S7:293-269. 51aging'sptem
5. !Sosnow)ri M. Loss&al D. Fodder& L. Revem ibility of opioid insensitive pain. Seventh World Congress on Pain in Paris. August 22-27, i993:16. 6. Slogoff S, Allen CW, Vessels LV. Cheney Dti. Clinical exprriencc with subanacsthetic lutaminc. Anesth Analg 1974;55:354-358. 7. Backonja Zimmermann
M, Amdt G, Gombar KA. Check B. M. Response of chronic neumpathic
pain gadtomes to kttaminc: a preliminary study. Pain l9%5&51-57. 8. Oye I. Mathisen L. Skjelbred P. Studies on effea of ketaminc a&gesia In neuropathic pain. !3tg~;~~~~~~~gress on Pain in Paris: August : . - . 9. Mexadante S. Intratbccal morphine and bupivacaine inadvanced cancer pain patients imp!antcd at home, J Pain Symptom Manage 1994+201-207. 10. codcrre TJ. Katz J. Yaccarino AL, Meback R. Contribution of cenval ncufoplasticity to path&y en: ~S~;fcu~ and experimental cvi;: L. Il. Dickensan AH, Sullivan AF. Differential effects of excitatory amino acid antagonist on dorsal horn nocicept&e neurons in the mt. Brain Rcs 19905006: 31-59. 14. White PF. Clinical uses of intravenous ones ~bctic and analgesic infusions. Ancsth Analg I* 8:371-177.
13. Yamamoto +I’,Yabh TL Comparison of the antinociceptive cffccts of the pre and post treatment with intrathccal morphine and MK801. an N?fDA antagonist on the formalin test in the rat. Anesthesiology 1992;77:757-X3. 14. Malbcrg AB, Yak& TL Spinal nitric oxide synthesis inhibition Mocks NMDA-induced thermal hypcralgcsia and produces antinociception in the formdin test in rats. Pam 1999~291-300. 15. Damr G, Hama A. Dcykin A. Vos B. Maciewicz R MK801 blocks the development of thermal induced hyperalgesia in a ran model of cxprimcntal painful neuropathy. Brain Res 1991:353:327so. 16. Mao J. Price DD, M;rycr DJ. 1.u J, Hayes RL. lntn~l:cc~l MK8Ul and Iucal nerve ancsthcua synrrgistically rcdrwc nuciccprive behaviors in rats with txprrimcnral pcriphctal mononcuropathy. Brain Rcs 1992;576:254-262.
17. Reich DL, Sihay C. Kctaminez an upd.~te on the fitst twenty&e years of clinical experience. Can J Anaesth 1989$6:186-197. 18. Twycross R. Pain relief in advanad cancer. Oxford. 1994~476-479. 19. Oshima E. Continuous subcutaneous injectitin of ktamine for cancer pain. Can J Anaesth 1990; 37:383-392. 20. Grant IS, Nimmo WS. McNicol LR Clements JA. Kctamine disposition in children and adults. Br J Anestl 1981;53:27-SO. 21. Elliot 1c Minami N, Koksnikov VA, Patemalt GW, lnturrisi CE. The NMDA receptor antagonists, LY2746!1 and MKSOI. and the nitric oxide synthasc inhibitor, NGnitrownine. attenuate analgcsic tolerance to the muopioid morphine but not to kappa opioids. Pain 19945689-75. 22. Mayer L, Miller RJ. Excitatory amino acid receptors, second messengers and regulation of intracellular Ca++ in mammalian neurons. In: Lodge D. CoIlingridge G, eds. The pharmacology of excitatory amino acids, Cambridge: Ehcv+crTrends, 199o:!t6-42. 29. Marck P, &n-Eliyahu S, Gold M. lebcskind JC. Excitatory amino acid antagonists (kynurenic acid and MK801) attenuirte the development of morphine tolerance in rat Brain Rcs 1991;547:177-181. 24. Trujillo KA. Akil H. Inhibition of morphine tolerance utd dependence by the NMDA receptor antagonist MK 801. Science 1991;51:85-87. 25. Foley KM. Changing concepts of tolerance IO opioids: what the cancer patient taught us. IASP Refresher Course Syllabus, Seventh World c011gms.s on Pain iu Paris; August 22-27, 1993:22l-255. ‘26. Cartwright PD, Ilcsa C. Jacksou AO. Myoclonur spasms following intnthecal diamorphine. J Pain Sympunn Manage 1993;8:492-495.