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√“¬ß“πºŸâªÉ«¬ : ¿“«–æ‘…∑“ß√–∫∫ª√– “∑®“°¡Õ√åøïπ∑’Ë„Àâ
§«∫§ÿ¡Õ“°“√ª«¥„πºŸâªÉ«¬¡–‡√Áß√–¬– ÿ¥∑⓬
ª“π„® Õ‘πæÿà¡ æ.∫.,*
æ߻忓√¥’ ‡®“±–‡°…μ√‘π æ.∫.*
Abstract :
Case report : Morphine induced neurotoxicity during pain control in terminal staged cancer patient
Inphum P, M.D.,* Chaudakshetrin P, M.D.*
*Pain Management Clinic, Department of Anesthesiology, Faculty of Medicine Siriraj Hospital,
Mahidol University, Bangkok 10700
A known case of 68 year-old female patient,
advanced stage cancer of pancreas, with opioid induced
neurotoxicity is described. She underwent distal pancreatectomy, colectomy and partial gastrectomy and has
failed to response to consecutive radiation treatment
and chemotherapy. Her initial presentation upon her
admission was partial gut obstruction and abdominal
discomfort but subsequently pulmonary metastasis
was found. After truth was told and advanced directive
counseling to her family, the parenteral nutrition catheterization was withheld and the palliative care goal
was re-determined, therefore an aggressive symptom
control was undertaken. Continuous morphine subcutaneous infusion was given, starting at the rate equivalent to previous opioid medication and titrated to the
patient needs. Bad dream and delirium was the first
sign of morphine toxicity found. Then involuntary
muscle twitching, myoclonus and involuntary movement occasionally occurred when the patient progressed to the dying. Haloperidol was given in combination
with morphine solution that infused subcutaneously or
occasionally withheld according to symptoms monitored. On the last 48 hours of her life, morphine
infusion was withdrew with provision of “as needed”
intravenous injection. The patient was progressively
decline and passed away peacefully.
√“¬ß“πºŸâªÉ«¬
¢Õß≈”‰ âÕÿ¥μ—π ·æ∑¬å®÷ß·π–π”„À⇢â“√—∫°“√„ à “¬ Port-A
Catheter ‡æ◊ËÕ„ÀâÕ“À“√‡¢â“∑“߇ âπ‡≈◊Õ¥ ·≈–ª√÷°…“„ÀâÀπ૬
√–ß—∫ª«¥√à«¡√—°…“Õ“°“√ª«¥®“°¡–‡√Áß
·√°√—∫∑’ËÀπ૬√–ß—∫ª«¥ ºŸâªÉ«¬√Ÿâ ÷°μ—«¥’ ¡’Õ“°“√
ª«¥·πàπ∫√‘‡«≥∑âÕß à«π∫π ÕàÕπ‡æ≈’¬ √—∫ª√–∑“πÕ“À“√‰¥â
πâÕ¬ ·≈–º–Õ◊¥º–Õ¡ Àπ÷Ëß —ª¥“Àå°àÕπ¡“‚√ß欓∫“≈ Õ“°“√
Keywords : neurotoxicity, opioid, myoclonus
Thai J Anesthesiology 2009 : 35(3) : 214-20.
ºŸâªÉ«¬À≠‘߉∑¬À¡â“¬ Õ“¬ÿ 68 ªï «‘π‘®©—¬«à“‡ªìπ
¡–‡√Á ß μ— ∫ Õà Õ π ‰¥â √— ∫ °“√ºà “ μ— ¥ distal pancreatectomy,
colectomy and partial gastrectomy ·≈–©“¬√—ß ’√à«¡°—∫‡§¡’
∫”∫—¥‡æ◊ËÕ√—°…“‚√§ ·μà‰¡àμÕ∫ πÕß ·≈–¡’¡–‡√Áß°√–®“¬‰ª
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214
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Vol. 35, No.3, July-September 2009
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Õ“°“√¢Õß morphine induced neurotoxicity ®÷ßÀ¬ÿ¥À¬¥¬“
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Thai Journal of Anesthesiology
215
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∑’Ëπ‘¬¡„™â√–ß—∫ª«¥ ‚¥¬„™â ”À√—∫√–ß—∫ª«¥®“°¡–‡√Áß ·≈–
”À√—∫§«“¡ª«¥‡√◊ÈÕ√—ß∑’ˉ¡à„™à®“°¡–‡√Áß Õ“°“√¢â“߇§’¬ß¢Õß
¬“∑’Ëæ∫‰¥â∫àÕ¬ §◊Õ Õ“°“√§≈◊Ëπ‰ â Õ“‡®’¬π ∑âÕߺŸ° ªí “«–
≈”∫“° „π¢≥–∑’Ë°“√°¥°“√À“¬„®æ∫‰¥âπâÕ¬°«à“ ·μà¡—° √â“ß
§«“¡°—ß«≈„Àⷰຟℙ⠇π◊ËÕß®“°‡ªìπ¿“«–·∑√°´âÕπ∑’ËÕ—πμ√“¬
∂÷ß·°à™’«‘μ „π¢≥–∑’Ë¿“«–·∑√°´âÕπ∑“ß√–∫∫ª√– “∑ (neurotoxicity) ∑’Ë¡—°®– ”·¥ß„π√Ÿª¢ÕßÕ“°“√ ‡™àπ allodynia,
Ë ∫‰¥â∫Õà ¬°«à“
hyperalgesia, myoclonus, seizure ‡ªìπÕ“°“√∑’æ
‚¥¬‡©æ“–∂Ⓣ¥â√—∫ª√‘¡“≥¡“°‡¢â“∑“ß°√–· ‡≈◊Õ¥ À√◊Õ„™â
‡æ◊ÕË ∫√√‡∑“Õ“°“√ª«¥®“°¡–‡√Áß ·μà°≈—∫‰¡àæ∫„π√“¬ß“πÀ√◊Õ
æ∫·μàπâÕ¬4-9
Morphine ∂Ÿ° °—¥®“°Ωîòπ §√—Èß·√°„πªï §.». 1806
‡ªìπ “√ phenanthrene alkaloid ¡’ Ÿμ√‚§√ß √â“ߥ—ß· ¥ß„π
√Ÿª∑’Ë 1
Morphine ®–∂Ÿ°‡ª≈’ˬπ‡ªìπ “√‡¡μ“∫Õ‰≈∑å∑’Ëμ—∫
‚¥¬°“√ conjugation °—∫ uridine diphosphate-glucuronic
acid (UDPGA) ‰¥â‡ªìπ morphine-3-glucuronide (M3G)
·≈– morphine-6-glucuronide (M6G) ‚¥¬¢÷Èπ°—∫«à“ªØ‘°‘√‘¬“
®–‡°‘¥¢÷Èπ∑’Ëμ”·Àπàߧ“√å∫Õπ∑’Ë 3 À√◊Õ 6 ª√–¡“≥√âÕ¬≈–
44-55 ¢Õß morphine ®–∂Ÿ°‡ª≈’Ë¬π‰ª‡ªìπ M3G, √âÕ¬≈– 910 ®–∂Ÿ°‡ª≈’Ë¬π‰ª‡ªìπ M6G ·≈–√âÕ¬≈– 8-10 ®–∂Ÿ°¢—∫ÕÕ°
∑“߉μ„π√Ÿª‡¥‘¡10-11 ”À√—∫ “√‡¡μ“∫Õ‰≈∑åÕ◊Ëπ Ê ‰¥â·°à
morphine-3,6-diglucuronide ·≈– morphine-3-etheral
sulfate12 ¥—ß· ¥ß„π√Ÿª∑’Ë 2
‡¡◊ËÕ„Àâ morphine ¥â«¬«‘∏’À¬¥‡¢â“™—Èπ„μ⺑«Àπ—ßÕ¬à“ß
μàÕ‡π◊ËÕß √à“ß°“¬®–¥Ÿ¥´÷¡ morphine ª√–¡“≥√âÕ¬≈– 80,
¥Ÿ¥´÷¡ M3G ·≈– M6G Õ’°√âÕ¬≈– 7013
M6G ‡ªìπ “√∑’Ë¡’ƒ∑∏‘Ï√–ß—∫ª«¥¡“°°«à“ morphine
Figure 1 Chemical structure of morphine, morphine-3-glucuronide (M3G)
216
«‘ —≠≠’ “√
·≈– morphine-6-glucuronide (M6G)
ªï∑’Ë 35 ©∫—∫∑’Ë 3 °√°Æ“§¡-°—𬓬π 2552
Figure 2 The metabolism of morphine
·μàƒ∑∏‘ÏÕ◊Ëπ Ê §≈⓬°—∫ morphine ”À√—∫ M3G ®–¡’ƒ∑∏‘Ï
∫“ßÕ¬à“ßμ√ߢⓡ°—∫ morphine ·≈– M6G ‡™àπ ‰¡à¡’ƒ∑∏‘Ï
√–ß—∫ª«¥ πÕ°®“°π’È morphine ·≈– M3G “¡“√∂∑”„À⇰‘¥
hyperalgesia, allodynia, myoclonus ·≈–¡’§ÿ≥ ¡∫—쑇ªìπ
neuroexcitants ‚¥¬ M3G ÕÕ°ƒ∑∏‘ω¥â·√ß°«à“ morphine ∂÷ß
10 ‡∑à“14-16 M3G ·≈– morphine “¡“√∂ºà“π blood brain
barrier ‡¢â“‰ª„π ¡Õ߉¥â ∑”„À⺟âªÉ«¬¡’Õ“°“√°√–μÿ° ™—° ·≈–
¡’Õ“°“√∑“ß ¡ÕßÕ◊Ëπ Ê ‰¥â √–¥—∫¢Õß morphine ·≈– M3G
„π ¡Õß®– Ÿß¢÷Èπ ∂â“√–¥—∫¢Õß “√‡À≈à“π’È„π°√–· ‡≈◊Õ¥¡’
ª√‘¡“≥ Ÿß17 ªí®®—¬ à߇ √‘¡¿“«–π’È ‰¥â·°à °“√∑”ß“π¢Õßμ—∫
·≈–‰μ À“°¡’§«“¡º‘¥ª°μ‘¢Õßμ—∫ °Á®–‰¡à “¡“√∂‡ª≈’ˬπ
morphine ‡ªìπ‡¡μ“∫Õ‰≈∑剥âμ“¡ª°μ‘ À“°‡ªìπ‚√§‰μ °Á®–
¢—∫∂à“¬ “√‡À≈à“π’ÈÕÕ°‰ª‰¥âπâÕ¬°«à“ª°μ‘18 πÕ°®“°π’Ȭ—ßÕ“®
¢÷Èπ°—∫‡™◊ÈÕ™“μ‘ æ∫«à“™“«®’π¡’°“√‡ª≈’ˬπ morphine ‰ª‡ªìπ
M3G ·≈– M6G ‰¥â¡“°°«à“ª°μ‘19 °“√‰¥â√—∫¬“∫“ß™π‘¥Õ“®
¡’º≈μàÕ‡¡μ“∫Õ‰≈∑å¢Õß morphine ‡™à𠬓 oxapam ¬—∫¬—Èß
morphine conjugation,20 ranitidine ≈¥ plasma M3G : M6G
í À“„π°“√¢—∫∂à“¬ “√‡À≈à“π’È
â «É ¬ ŸßÕ“¬ÿ®–¡’ª≠
ratio21 ·≈–„πºŸª
ÕÕ°‰ª®“°√à“ß°“¬
ºŸâªÉ«¬√–¬– ÿ¥∑⓬®–¡’°“√∑”ß“π¢Õßμ—∫·≈–‰μº‘¥
ª°μ‘ ∑”„Àâ¡’°“√¢—∫∂à“¬ “√μà“ß Ê ≈¥≈ß ·¡â∫“ߧ√—Èߺ≈°“√
μ√«®°“√∑”ß“π¢Õßμ—∫ ‰μ®–ª°μ‘ ·μà°Á¡’‚Õ°“ æ∫°“√ – ¡
¢Õß morphine, M3G ·≈– M6G ‰¥â22
ºŸâªÉ«¬√“¬π’È¡’Õ“°“√∑’Ë· ¥ß∂÷ß¿“«– neurotoxicity
‰¥â·°à Õ“°“√¡◊Õ —Ëπ ¡◊Õ°√–μÿ° ∫“ߧ√—È߇§≈◊ËÕπ‰À«‚¥¬‰¡à¡’®ÿ¥
À¡“¬ ´÷Ë߇¡◊ËÕÀ¬ÿ¥„Àâ morphine Õ“°“√¥—ß°≈à“«√«¡∑—ÈßÕ“°“√
Vol. 35, No.3, July-September 2009
®÷ߥ’¢÷Èπ à«π„À≠à¿“«– neurotoxicity ¡—°®–æ∫„π
ºŸâªÉ«¬∑’ˉ¥â√—∫ morphine ¥â«¬«‘∏’©’¥ ®“°√“¬ß“π¢Õß Potter4
æ∫ºŸâªÉ«¬∑’ˉ¥â√—∫ morphine ª√‘¡“≥¡“°°«à“ 500 ¡‘≈≈‘°√—¡
μàÕ«—π ®”π«π 19 §π „π®”π«ππ’È 12 §π‡°‘¥Õ“°“√°≈â“¡‡π◊ÈÕ
°√–μÿ° (myoclonus) πÕ°®“°π’¬È ß— æ∫¿“«–π’„È πºŸ∑â ‰’Ë ¥â√∫— morphine ‚¥¬«‘∏’Õ◊Ëπ Ê ‡™àπ ‡¢â“À≈Õ¥‡≈◊Õ¥¥” ‡¢â“™àÕ߉¢ —πÀ≈—ß
‡¢â“™—Èπ„μ⺑«Àπ—ßÕ¬à“ßμàÕ‡π◊ËÕß·≈–«‘∏’°‘π23-28 ‡ªìπμâπ ”À√—∫
°≈‰°∑’Ë∑”„À⇰‘¥¿“«– neurotoxicity ¬—߉¡à∑√“∫·πà™—¥ ‡™◊ËÕ
«à“¡’°“√¬—∫¬—Èß glycinergic „π‰¢ —πÀ≈—ß„Àâ∑”ß“ππâÕ¬≈ß29
(glycinergic §◊Õ “√∑’‡Ë °’¬Ë «¢âÕß°—∫°“√π”¢Õß°√–· ª√– “∑)
À√◊ Õ Õ“®‡ªì π ‡æ√“–¡’ ° “√°√–μÿâ π N-methyl-D-aspartate
(NMDA) receptor „π√–∫∫ª√– “∑6,15,30,31
ª√‘¡“≥ morphine ∑’Ë∑”„À⺟âªÉ«¬√“¬π’È¡’Õ“°“√¢Õß
neurotoxicity ‡∑à“°—∫ 48 ¡‘≈≈‘°√—¡ ´÷Ëßπ—∫«à“‰¡à„™àª√‘¡“≥∑’Ë Ÿß
·μà¿“«– neurotoxicity ‡°‘¥¢÷Èπ‰¥â‡æ√“–ºŸâªÉ«¬√—∫ª√–∑“π
Õ“À“√‰¥âπâÕ¬ ·≈–ÕàÕπ‡æ≈’¬ ¡“‡ªìπ‡«≈“π“π √à«¡°—∫Õ“°“√
§≈◊Ëπ‰ â Õ“‡®’¬π ·≈–∑âÕߺŸ° ¥—ßπ—Èπ®÷ß¡’¿“«–¢“¥πÈ” ¿“«–
‚´‡¥’¬¡μË” „π√–¬–μàÕ¡“¿“«–¢“¥πÈ”·≈–‚´‡¥’¬¡μË”‡ªìπ
ªí≠À“¡“°¢÷Èπ ‡π◊ËÕß®“°¡’°“√ Ÿ≠‡ ’¬‰ª∑“ß “¬ nasogastric
tube ®÷߇ªìπªí®®—¬ à߇ √‘¡„À⇰‘¥¿“«– neurotoxicity Õ’°∑—Èß
ºŸâªÉ«¬¡–‡√Áß√–¬– ÿ¥∑⓬¡—°¡’§«“¡∫°æ√àÕߢÕßÀπâ“∑’Ëμ—∫·≈–
‰μ ®÷߇°‘¥°“√ – ¡¢Õß morphine ·≈–‡¡μ“∫Õ‰≈∑å¢÷Èπ22 ∂÷ß
·¡â«à“„π√–¬–π’ȺŸâªÉ«¬®–¡’ªí “«–ÕÕ°¥’ ·μà‰¡àÕ“®√–∫ÿ§«“¡
º‘¥ª°μ‘¢Õß‰μ‰¥â™¥— ‡®π ´÷ßË ∂◊Õ«à“‰¡à¡§’ «“¡®”‡ªìπ„π°“√æ‘ ®Ÿ πå
¢âÕ‡∑Á®®√‘ßπ’È
”À√—∫°“√¥Ÿ·≈√—°…“§«√‡√‘Ë¡¥â«¬°“√μ√–Àπ—°∂÷ß
delirium
Thai Journal of Anesthesiology
217
°“√‡°‘¥¿“«– neurotoxicity „πºŸâªÉ«¬∑’Ë¡’§«“¡‡ ’Ë¬ß Ÿß §«√
√–¡—¥√–«—ß ·≈–„Àâ°“√ªÑÕß°—π ‡ΩÑ“√–«—ß Õ∫∂“¡√“¬≈–‡Õ’¬¥
¢ÕßÕ“°“√®“°ºŸâªÉ«¬·≈–ºŸâ¥Ÿ·≈ ‡æ◊ËÕ„Àâ«‘π‘®©—¬‰¥â‡√Á« ·≈–À“°
‡ÀÁπ«à“¡’§«“¡®”‡ªìπ§«√≈¥¢π“¥ morphine ∑’Ë„ÀⷰຟâªÉ«¬
À√◊ÕÕ“®À¬ÿ¥¬“32 πÕ°®“°π’ȧ«√ —Ë߬“·°âª«¥„Àâ©’¥À√◊Õ°‘π
‰«â‡º◊Ëՙ૬‡À≈◊Õ‡«≈“¡’Õ“°“√ ∫“ß ∂“π°“√≥åÕ“®®”‡ªìπμâÕß
≈—∫™π‘¥¬“·°âª«¥ (opioid rotation)33,34 À√◊Õ‡ª≈’ˬπ«‘∏’°“√
„Àâ (switching route of administration)32 ´÷Ëß«‘∏’¥—ß°≈à“«§«√
μâÕß –¥«°„π°“√§«∫§ÿ¡ª√‘¡“≥¢Õ߬“ ·≈–À“°μâÕß°“√À¬ÿ¥
°“√„À⬓ °Á§«√ “¡“√∂∑”‰¥â·≈–‡°‘¥º≈¢÷Èπ∑—π∑’ πÕ°®“°π—Èπ
§«√≈¥ªí®®—¬∑’Ë à߇ √‘¡„À⇰‘¥¿“«– neurotoxicity ‡™àπ ¿“«–
¢“¥πÈ” À√◊Õ¿“«–‡°≈◊Õ·√ຑ¥ª°μ‘
¬“∫“ß™π‘¥ ‡™àπ midazolam ·≈– haloperidol ∑’Ë„Àâ
·°àºŸâªÉ«¬„π√–¬– ÿ¥∑⓬ ‡ªìπ°“√„Àâ‡æ◊Ëՙ૬‡À≈◊ÕÕ“°“√‰¡à
ÿ¢ ∫“¬ Õ“°“√°√–μÿ° (myoclonus) Õ“°“√πÕπÀ≈—∫‰¡à
π‘∑ À√◊ÕÕ“°“√ delirium ∑’ˇ°‘¥¢÷Èπ∫“ß™à«ß ”À√—∫¬“™π‘¥
Õ◊Ëπ∑’ËÕ“®„™â‡æ◊ËÕ√—°…“Õ“°“√°√–μÿ° (myoclonus) ‰¥â·°à baclofen, diazepam, clonazepam, valproic acid ·≈– dantrolene
sodium33 ‡ªìπμâπ ºŸâªÉ«¬√–¬– ÿ¥∑⓬¡’‚Õ°“ ‡ ’ˬßμàÕª√‘¡“≥
¬“ morphine ∑’ Ë ßŸ ‡°‘π®“°°“√ – ¡ ∑”„À⇰‘¥Õ“°“√ delirium
«‘∏’°“√ª√—∫„À⬓·°àºŸâªÉ«¬§«√®–‡ªìπ«‘∏’∑’ˬ◊¥À¬ÿàπ‰¥â μ—«Õ¬à“ß
‡™àπ «‘∏’°“√„À⬓լà“ßμàÕ‡π◊ËÕß·°àºŸâªÉ«¬√“¬π’È ∑’Ë„Àâ ≈—∫À¬ÿ¥
‡ªìπ√–¬– ·≈–°“√μ‘¥μ“¡Õ“°“√∑’ËÕ“®μâÕß∑”∂’Ë¢÷Èπ‡¡◊ËÕ‡¢â“ Ÿà
√–¬– ÿ¥∑⓬
√ÿª
°“√∫√‘∫“≈ºŸâªÉ«¬¡–‡√Áß√–¬– ÿ¥∑⓬ (palliative
care) À¡“¬∂÷ß°“√¥Ÿ·≈∑’˧√Õ∫§≈ÿ¡·≈–‡∫Á¥‡ √Á® ∑—Èß√à“ß°“¬
·≈–®‘μ„® ´÷ßË ¡—°®–ª√–°Õ∫¥â«¬°“√√—°…“Õ“°“√‡®Á∫ª«¥æ√âÕ¡
∑—ßÈ Õ“°“√Õ◊πË Ê ∑’¡Ë „’ Àâ≈¥≈ß √à«¡°—∫°“√„À⧔ª√÷°…“·≈– ◊ÕË “√
Õ¬à“ß¡’ª√– ‘∑∏‘¿“æ ®ÿ¥ª√– ߧåÀ≈—°‡æ◊ËÕ„À⺟âªÉ«¬´÷Ëß„°≈â®–
‡ ’¬™’«‘μ∑ÿ°¢å∑√¡“ππâÕ¬∑’Ë ÿ¥ ·≈–‡¡◊ËÕ∂÷߇«≈“∑’Ë ¡§«√°Á„Àâ
®“°‰ªÕ¬à“ß ß∫À√◊ÕÕ’°π—¬Àπ÷Ëߧ◊Õ ç쓬¥’é (Good death)
Õ¬à“߉√°Áμ“¡ „π°“√∫√‘∫“≈ ºŸâªÉ«¬√–¬– ÿ¥∑⓬¡—°®–¡’™à«ß∑’Ë
®”‡ªìπμâÕ߉¥â√—∫ morphine ‡ ¡Õ ·≈–ºŸâªÉ«¬¡—°¡’‚Õ°“ ∑’Ë®–
‡°‘¥¿“«– neurotoxicity ‰¥â Ÿß ·¡â«à“®–‰¥â√—∫¬“„πª√‘¡“≥
ª°μ‘ À“°¡’¿“«–¢“¥πÈ” ¢“¥‡°≈◊Õ·√à„π√à“ß°“¬ ‰μÀ√◊Õμ—∫
∑”ß“ππâÕ¬≈ß °“√‡ΩÑ“√–«—ß∑’Ë„°≈♑¥®÷߇ªìπ ‘Ëß®”‡ªìπ„πºŸâªÉ«¬
∑’Ë¡’§«“¡‡ ’ˬ߇À≈à“π’È °“√·°â‰¢¿“«– neurotoxicity §«√‡√‘Ë¡
218
«‘ —≠≠’ “√
∑’ Ë “‡Àμÿ ßà ‡ √‘¡„À⇰‘¥Õ“°“√ √à«¡°—∫°“√≈¥ª√‘¡“≥¬“ opioid
¡’√“¬ß“π«à“°“√‡ª≈’ˬπ™π‘¥¬“·°âª«¥ (opioid rotation) À√◊Õ
‡ª≈’ˬπ«‘∏’„Àâ (switching route of administration) √à«¡°—∫
°“√√—°…“μ“¡Õ“°“√®–™à«¬≈¥¿“«–æ‘…∑“ß√–∫∫ª√– “∑‰¥â
∂â“®”‡ªìπÕ“®À¬ÿ¥°“√„Àâ morphine ‰«â™—Ë«§√“« ¥—߇™àπºŸâªÉ«¬
√“¬π’È
‡Õ° “√Õâ“ßÕ‘ß
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