Reduction in Constipation and Laxative Requirements Following Opioid Rotation to Methadone: A Report of Four Cases

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1 Vol. 18 No. 4 October 1999 Journl of Pin nd Symptom Mngement 303 Clinicl Note Reduction in Constiption nd Lxtive Requirements Following Opioid Rottion to Methdone: A Report of Four Cses Pul J. Deninck, MD, MSc, FRCPC, nd Edurdo Bruer, MD Pllitive Cre Progrm, Grey Nuns Community Helth Centre, nd Division of Pllitive Cre Medicine, University of Albert, Edmonton, Albert, Cnd Abstrct Constiption is common symptom in cncer ptients, especilly in those who re receiving opioid nlgesics for pin. Although severl rticles hve recently exmined constiption with respect to custion nd tretment, little reserch hs been done to elucidte the effects of different opioids on the bowel. Recent reserch hs found tht lxtive doses my be lower in ptients using methdone s n nlgesic, but chnges in constiption were not mesured. We report here on four cses in which ptients hd improvement in constiption nd decresed lxtive requirements following opioid rottion to methdone. J Pin Symptom Mnge 1999;18: U.S. Cncer Pin Relief Committee, Key Words Cncer pin, opioid rottion, methdone, constiption, lxtives Introduction Constiption is common symptom in dvnced cncer ptients. Studies hve demonstrted tht 40 to 80% of ptients on pllitive cre service hve constiption. 1,2 This proportion increses to 90% when ptients re treted with opioids. 2,3 Severl recent review rticles hve exmined this problem 2,4,5 with respect to custion nd tretment. However, little reserch hs been done on the differentil effects of the vrious opioid gonists on constiption in the terminlly ill cncer ptient. Methdone is gining populrity s n opioid Dr. Deninck is McEchern Fellow of the Cndin Cncer Society. Address reprint requests to: Edurdo Bruer, MD, Dept. of Symptom Control nd Pllitive Cre, University of Texs, M.D. Anderson Cncer Center, 1515 Holcombe Blvd., Houston, Texs 77030, USA. Accepted for publiction: December 8, nlgesic becuse of its widespred vilbility, low cost, nd long hlf-life, which decreses the need for multiple dily doses. 6 9 Its lck of ctive metbolites is useful for those ptients with opioid-induced neurotoxicity, 10 nd its N-methyl-Dsprtte (NMDA) receptor-ntgonist ctivity my be cliniclly importnt for ptients with neuropthic pin. 11,12 However, there hve been no reports of improvement in opioid-induced constiption with the use of methdone. A retrospective study hs found tht lxtive doses were significntly lower in ptients using methdone s n nlgesic, 13 but chnges in constiption were not mesured. We report here on four cses where opioid rottion to methdone ws followed by drmtic improvement in constiption nd reduced need for lxtives. Ptients Cse 1 A 51-yer-old womn ws dmitted for opioid rottion to methdone. She hd been dig- U.S. Cncer Pin Relief Committee, /99/$ see front mtter Published by Elsevier, New York, New York PII S (99)00086-X

2 304 Deninck nd Bruer Vol. 18 No. 4 October 1999 nosed with ductl crcinom of the left brest with nodl involvement 21 months prior to this dmission. She pursued lterntive therpies until inflmmtory chnges involving the left brest nd chest wll ppered 13 months prior to dmission. Metstses to the liver nd lung were lso found. She underwent segmentl brest resection, followed by nthrcyclinebsed chemotherpy nd rdiotherpy (RT), which produced prtil response. Within 1 month, RT ws gin dministered to tret the rpid onset of inflmmtory chnges to the right brest. She ws ssessed t the Pin nd Symptom outptient clinic 5 months prior to dmission nd ws found to hve mixed (viscerl nd neuropthic) pin syndrome involving the right thorx, which ws thought to be relted to the cncer recurrence nd subsequent tretment. This ws treted with longcting morphine. One week lter, rpid dose escltion without pin relief preceded opioid rottion to hydromorphone. One month lter, dexmethsone ws dded, which decresed brekthrough opioid requirements. Three months prior to dmission, docetxel chemotherpy ws strted for symptomtic relief of incresed pin nd swelling of both brests. Symptomtic response ws noted but febrile neutropeni with typicl pneumoni nd hospitliztion fter the third dose (6 weeks prior to dmission) cused suspension of tretment. She ws found to hve mlignnt pleurl effusion, which ws drined by thorcocentesis. She ws tking 216 mg of long-cting hydromorphone orlly twice dily nd hd tken 7 to 8 brekthrough doses of 48 mg ech (totl dily dose of pproximtely 816 mg). The ptient s pin becme more severe nd she ws gin ssessed in the Pin nd Symptom outptient clinic. Her opioids were incresed to 254 mg long-cting hydromorphone nd her brekthrough ws incresed to 80 mg. She ws dmitted to the Tertiry Pllitive Cre Unit the next dy. She dmitted to drowsiness, but denied ny other symptoms of opioidinduced neurotoxicity. Other symptoms on dmission included dyspne nd constiption. Her Mini-Mentl Sttus Exmintion (MMSE) 14 ws 30/30 (bseline 28). Her lst bowel movement ws 2 dys prior to dmission. The ptient s bowel history prior to opioids ws one bowel movement dily. Since strting on the opioid nlgesics, she continued to hve bowel movement every 1 2 dys. An bdominl rdiogrph reveled mssive constiption: the lumen of the colon ws completely occupied by stool (constiption score 12/12 15,16 ). She hd been on docuste clcium 240 mg twice dily, sennosides 25.8 mg (3 tblets) twice dily, nd biscodyl 10 mg t night (Tble 1). On the dy of dmission (Dy 0), she ws switched to methdone, her lxtives were incresed, nd clensing enem ws given. However, from Dy 2 to 4, the ptient hd on verge 3 lrge explosive bowel movements per dy. She refused her lxtives on Dy 3 but resumed them soon fterwrd, nd therefter hd n verge of 1.4 bowel movements dily. The ptient s pin quickly cme under better control, s evidenced by decrese in her pin scores (Dy 0: 3/10; Dy 5: 1/10), decrese in her opioid intke (Tble 1), nd n increse in her mobility. Her course ws complicted by lymphngitic metstsis to the lungs, which cused worsening dyspne nd led to n escltion in the methdone dose for symptomtic control. The ptient developed delirium on Dy 46 nd ws rotted to hydromorphone with little chnge. She died quietly on Dy 48. Cse 2 A 60-yer-old mn ws dmitted with confusion nd poor pin control. He ws dignosed pproximtely 2 yers prior to dmission with Ptients Tble 1 Chnges in Constiption nd Lxtives with Rottion to Methdone DLD premethdone DLD postmethdone BM/d premethdone BM/d postmethdone MEDD premethdone MEDD postmethdone Cse ,000 1,110 Cse , Cse Cse , Abbrevitions: DLD dily lxtive dose; BM bowel movements; MEDD morphine equivlent dily dose (in mg). Vlues re verges from dmission.

3 Vol. 18 No. 4 October 1999 Lxtive Use nd Opioid Rottion to Methdone 305 denocrcinom of the prostte, with widespred metstses to his xil skeleton. He received tril of hormonl tretment, which ws unsuccessful in decresing the spred of bony metstsis or lleviting the pin. In the 3 months preceding dmission, he underwent two seprte courses of pllitive rdiotherpy to his pelvis, which gve t best temporry pin relief. One week prior to dmission, despite cycle of pllitive chemotherpy, he required dmission to nother fcility for pin control. He ws trnsferred to our Tertiry Pllitive Cre Unit with mixed pin syndrome (bony nd neuropthic, thought to be due to nerve impingement), which hd led to rpid escltion in the dose of hydromorphone nd crbmzepine. He lso ws experiencing confusion nd dizziness. Despite frequent bowel movements, he reported feeling constipted. His norml bowel pttern hd been dily to every other dy while on lxtive preprtions (Tble 1). On dmission, he ws found to be confused despite hving MMSE of 26/30 (norml bseline of 24). This confusion ws thought to be due to opioids, nd rottion from hydromorphone to methdone ws initited. His rdiogrphic constiption score ws 11/12, nd he ws given clensing enem, which yielded lrge bowel movement. However, over the next 4 dys (corresponding to the opioid rottion), he hd on verge 3 loose bowel movements dily, despite being on tpering dosges of lxtives. For the reminder of his dmission, he hd on verge one bowel movement dily, while on only one-fourth of the previous lxtive dose (Tble 1). The ptient s confusion improved (MMSE 29/30) nd he chieved excellent pin control with the methdone, which ws reflected by decresed pin score (1/10, compred with n dmission score of 6/10) nd n increse in his mobility. He ws dischrged home fter 15 dys in hospitl, with 12-fold reduction in opioid dose nd 75% reduction in lxtive dose (Tble 1). Cse 3 A 72-yer-old womn ws trnsferred from her locl hospitl for ssessment of confusion nd poor pin control. She initilly presented 6 months prior to dmission with diplopi nd right-sided Bell s plsy, for which no cuse ws identified. Within the following 6 weeks, she developed swelling in the right neck nd submndibulr regions, nd ws dmitted to her locl hospitl for investigtion. Non-Hodgkin s lymphom, intermedite grde, ws dignosed following fine needle nd nodl biopsies, nd she received nthrcycline-contining chemotherpy, s well s intrthecl methotrexte for presumed centrl nervous system involvement. One month prior to dmission, she developed lethrgy, decresed level of consciousness nd bilterl leg pin, nd ws dmitted to her locl hospitl. A computerized tomogrm scn of the brin reveled n bnormlity in the left hemisphere, likely representing metsttic disese. She continued to hve poor pin control nd fluctuting level of consciousness, nd ws trnsferred to our Tertiry Pllitive Cre Unit. On dmission, further questioning reveled tht the ptient hd 40 pck-yer smoking history nd history of lcohol buse (CAGE* questionnire score of 2/4). 17 She ws on trnsderml fentnyl ptch nd ws tking hydromorphone orlly for brekthrough pin. She lso ws tking 2 different benzodizepines. The pin in her legs ws felt to be neuropthic in nture. She lso hd history of chronic difficulty with constiption nd hd been on long-term lxtives (Tble 1). Exmintion reveled the ptient to be drowsy, with bilterl lower limb wekness nd sensory chnges in the L3 L4 res consistent with spinl stenosis. Her MMSE ws 23/30 (norml bseline of 26). A constiption score, s obtined from n bdominl rdiogrph, ws 2/ 12. She ws hydrted, rotted to methdone, the benzodizepines were stopped, nd further pllitive tretment for the underlying mlignncy ws considered. During the opioid rottion, she developed dirrhe, nd hd dily verge of 1.7 bowel movements, which decresed only slightly postrottion nd with reduction in lxtives (Tble 1). Her MMSE improved to 28/30 on Dy 4, nd her pin score improved from 6/10 on dmission to 1/10 by * CAGE is n cronym for questionnire screening for lcohol buse: Cut down on drinking Annoyed by criticism of drinking Guilty bout drinking Eye-opener use (lcohol use first thing in the morning)

4 306 Deninck nd Bruer Vol. 18 No. 4 October 1999 Dy 7. She ws trnsferred to the locl cncer institute for further investigtions nd considertion of tretment of the lymphom on Dy 7. Cse 4 A 73-yer-old mn ws dmitted from home for pin nd symptom control, s well s need for psychosocil support. Approximtely 6 months prior to dmission, he developed erly stiety, weight loss, nd postprndil bck pin. Subsequent investigtions reveled pncretic mss on bckground of chronic clcific pncretitis, ccompnied by lymphdenopthy nd splenic nd mesenteric vein thrombosis. Biopsy of the mss ws positive for denocrcinom. Two months prior to dmission, he ws ssessed in the Pin nd Symptom outptient clinic for bdominl nd bck pin, norexi, nd constiption. A history of lcohol buse ws obtined (CAGE 2/4), nd his MMSE ws 30/30. His morphine nd bowel medictions (sennosides nd docuste sodium) were incresed, but he refused rottion to methdone t tht time. Three weeks prior to dmission, he continued to hve poorly controlled pin, nd developed hllucintions nd myoclonus t home. He ws ssessed by the regionl pllitive cre tem, who rotted him to hydromorphone nd gin incresed his lxtives. It ws lso felt tht he my be suffering from depression nd/or somtiztion. He ws ssessed 2 dys prior to dmission, t which time it ws felt his pin ws not improving nd hospitliztion ws recommended. On dmission, the ptient denied lcohol buse in the pst nd hd little insight into his current condition. He hd not hd bowel movement for 6 dys. His MMSE ws 28/30 (norml bseline 26) nd he ws lert nd pproprite. His exmintion ws remrkble for bdominl fullness with reproducible pin nd digitl exm showed the rectum to be empty of stool. His rdiogrphic constiption score from n bdominl rdiogrph ws 5/12. His hydromorphone ws incresed nd his lxtives continued t the sme dose, but by Dy 3 he hd only one bowel movement nd ws experiencing hllucintions nd myoclonus. Opioid rottion to methdone ws initited nd his lxtives were incresed. His pin ws better controlled, s evidenced by improvement in the pin score nd incresed mobility. The frequency of his bowel movements did not chnge despite decresing nd subsequently discontinuing his lxtives (Tble 1). His pin remined under good control nd his bowel movements were regulr until his sudden deth on Dy 36. Discussion Constiption is common symptom in dvnced cncer ptients, nd is reported by up to 90% of those ptients treted with opioid nlgesics. 3 Advnced cncer ptients hve mny risk fctors, including structurl bnormlities, metbolic disturbnces, neurologic disorders, dvnced ge, inctivity, poor intke, nd drug side effects. 4,5 However, constiption is often not ssessed, nd this leds to indequte tretment. A full ssessment should include history of bowel movements, both before nd fter opioid therpy, the symptoms due to constiption, nd physicl exmintion including digitl rectl exm. A retrospective review of dmissions to our pllitive cre unit 18 found tht 59% of ptients did not undergo rectl exmintion nd there ws miniml nd/or insufficient documenttion by both the medicl nd nursing stff regrding the symptoms relted to constiption. In ddition, simple bedside questions nd clinicl mneuvers my be poor predictors for the dignosis of constiption. 18 The dignosis cn be confirmed using the rdiogrphic constiption score. 15,16,18 The routine use of this score, s seen in these four cses, helps to identify those ptients who hve severe constiption nd require prompt tretment. The score is determined by the ssessment of the mount of stool in ech of the four bdominl qudrnts using the following system: 0 no stool, 1 stool occupying 50% of the lumen of the colon, 2 stool occupying 50% of the lumen, nd 3 stool completely occupying the lumen. The colon is scored out of 12, nd score 7/12 indictes severe constiption requiring immedite tretment. 5,18 Severl lxtive preprtions re vilble for the tretment of constiption. However, the different modes of ction nd the lck of equivlency tbles mkes it difficult to compre these medictions. Recent reviews recommend combintion of senn nd docuste s the initil tretment for opioid-induced constiption, with the ddition of lctulose nd mgnesium sulfte for reltively refrctory cses. For severe constiption, combintion of orl

5 Vol. 18 No. 4 October 1999 Lxtive Use nd Opioid Rottion to Methdone 307 lxtives, rectl suppositories, nd enems my be needed. 2,4 To compre these four cses, 8.6 mg senn, 100 mg docuste sodium, 5 mg biscodyl, nd 15 ml of lctulose were ech considered s one unit of lxtive. 13 Thus ptient on two tblets of senn nd two cpsules of docuste hd dily lxtive dose of 4 units. All of the reported ptients were tking t lest 6 units of lxtives dily, usully with poor results (Tble 1). After methdone rottion, ech ptient ws tking less lxtives, with more frequent bowel movements. Ech of our ptients required opioid rottion for opioid-induced neurotoxicity or dose escltion. In ech cse, methdone ws the opioid of choice for severl resons. First, ll of the ptients hd used severl opioid nlgesics with the result being either poor long-term pin control or toxicity. Three of the ptients required high doses of opioids ( 1200 morphine equivlent dily dose), two hd previous substnce buse histories, nd t lest 2 were felt to hve psychologic distress (somtiztion), ll of which re independent risk fctors for poor pin control Recent reports of NMDA receptor ntgonist ctivity by methdone my be cliniclly importnt for the tretment of neuropthic pin, 11,12 which ws found in 3 of the 4 ptients. Methdone hs reduced cross-tolernce to other opioid gonists, s well s high potency (equinlgesic conversion of 10 mg morphine to 1 mg methdone 6,23 ), which my lso ccount for the reduction of the morphineequivlent dily dose (MEDD). 5,22,23 Neuropthic pin syndromes, s seen in 3 of our 4 ptients, often re treted with opioids s well s vriety of djuvnt medictions. 24,25 Severl of these commonly used drugs my in fct worsen constiption in dvnced cncer ptients. Medictions with nticholinergic ctivity (ntidepressnts, ntispsmodics, nd phenothizines), nticonvulsnts (e.g., crbmzepine), nd ntihypertensives (e.g., clonidine) hve been ssocited with constiption. 5 The pproch of our group is to mximize the benefits of opioid nlgesics, using those tht my hve intrinsic NMDA receptor ctivity (methdone) 11,12 nd mke liberl use of corticosteroids, which when used for short periods to chieve pin control re not ssocited with severe side effects. 26 Why did our ptients hve such remrkble chnges in their bowel function following rottion to methdone? The overll reduction in the MEDD, due to the incomplete opioid cross-tolernce, my hve cused reduced opioid effects on the bowel 13 but continued to give good pin relief. The use of fentnyl for the tretment of cncer pin hs lso been ssocited with less gstrointestinl side effects, including constiption, but there hve been severl cse reports of ptients demonstrting withdrwl symptoms fter rottion to trnsderml fentnyl These symptoms included bdominl crmping or pin, dirrhe, nuse, nxiety, shivering, chnges in hert rte nd blood pressure, nd formiction. Our ptients hd dirrhe nd two complined of trnsient bdominl crmping, but no other evidence of opioid withdrwl. Like fentnyl, methdone is lso lipophilic nd is highly distributed to the body tissues. This llows peripherl reservoir effect 37 which my llow for decresed mintennce doses. These smller doses my exert less ctivity on opioid receptors in the gstrointestinl trct nd cuse n incomplete withdrwl syndrome to occur. An lterntive explntion my be tht methdone, like fentnyl, my hve different ffinity for the opioid receptors in the gut, thus cusing less gstrointestinl symptoms. 35,36 A report of orl ptient-controlled methdone which ws effective in mnging bdominl pin without worsening the known chronic prtil bowel obstruction in two dvnced cncer ptients suggests tht methdone my be useful in ptients with n ltertion in bowel motility. 38 Opioid rottion for toxicity is not new concept, nd severl cse series nd retrospective reviews re present in the literture. 10,39,40 Rottion to lterntive opioids usully helps in the resolution of neurotoxic side effects nd my llow reduction in the nlgesic dose. However, no reports of opioid rottion hving beneficil effects for constiption exist. A retrospective study of the clinicl predictors of lxtive dose in dvnced cncer ptients reveled tht ptients on methdone hd lower effective lxtive doses thn ptients on other opioids, 13 but the study did not show chnge in postopioid rottion, s seen in the present four ptients. In conclusion, the reduction in lxtive dose nd improvement in constiption in these four

6 308 Deninck nd Bruer Vol. 18 No. 4 October 1999 ptients following opioid rottion to methdone suggests nother option for tretment of refrctory constiption. Rottion to methdone my lso be beneficil for improved pin control with less risk for opioid-induced neurotoxicity. References 1. Curtis EB, Krech R, Wlsh TD. Common symptoms in ptients with dvnced cncer. J Pllit Cre 1991;7: Sykes NP. Constiption nd dirrhe. In: Doyle D, Hnks G, McDonld N, eds. Oxford textbook of pllitive medicine. Oxford: Oxford University Press, 1998: Twycross RG, Lck SA. Symptom control in fr dvnced cncer: pin relief. London: Pitmn, 1983: Derby S, Portenoy RK. Assessment nd mngement of opioid-induced constiption. In: Portenoy RK, Bruer E, eds. Topics in pllitive cre, Vol. 1. Oxford: Oxford University Press, 1997: Mncini I, Bruer E. Constiption in dvnced cncer ptients: review. Support Cre Cncer 1998;6: Ripmonti C, Zecc E, Bruer E. An updte on the clinicl use of methdone for cncer pin. Pin 1997;70: De Conno F, Groff L, Brunelli C, Zecc E, Ventfridd V, Ripmonti C. Clinicl experience with orl methdone dministrtion in the tretment of pin in 196 dvnced cncer ptients. J Clin Oncol 1996;14: Vigno A, Fn D, Bruer E. Individulized use of methdone nd opioid rottion in the comprehensive mngement of cncer pin ssocited with poor prognostic indictors. Pin 1996;67: Bruer E, Wtnbe S, Finsinger RL, Spchynski K, Surez-Almzor M, Inturrisi C. Custom-mde cpsules nd suppositories of methdone for ptients on high-dose opioids for cncer pin. Pin 1995;62: Deninck PJ, Bruer E. Opioid use in cncer pin: Is more liberl pproch enhncing toxicity? Act Anesthesiol Scnd (in press). 11. Gormn AL, Elliott KJ, Inturrisi CE. The d- nd l-isomers of methdone bind to the non-competitive site on the N-methyl-D-sprtte (NMDA) receptor in rt forebrin nd spinl cord. Neurosci Lett 1997; 223: Ebert B, Andersen S, Krogsgrd-Lrsen P. Ketobemidone, methdone nd pethidine re non-competitive N-methyl-D-sprtte (NMDA) ntgonists in the rt cortex nd spinl cord. Neurosci Lett 1997; 223: Mncini I, Hnson J, Bruer E. Opioid type nd other clinicl predictors of lxtive dose in dvnced cncer ptients: retrospective study [bstrct]. J Pin Symptom Mnge 1998;15:S Folstein MF, Folstein S, McHugh P. Mini-mentl stte : prcticl method for grding the cognitive stte of ptients for the clinicin. J Psych Res 1975;12: Strreveld JS, Pols MA, Vn Wijk HJ, Bogrd JW, Poen H, Smont AJPM. The plin bdominl rdiogrph in the ssessment of constiption. 2. Gstroenterology 1990;28: Smith RG, Lewis S. The reltionship between digitl exmintion nd bdominl rdiogrphs in elderly ptients. Age Ageing 1990;9: Ewing J. Detecting lcoholism: the CAGE questionnire. J Am Med Assoc 1984;252: Bruer E, Surez-Almzor M, Velsco A, Bertolino M, Mcdonld SM, Hnson J. The ssessment of constiption in terminl cncer ptients dmitted to pllitive cre unit: retrospective review. J Pin Symptom Mnge 1994;9: Bruer E, Mcmilln K, Hnson J, McDonld RN. The Edmonton stging system for cncer pin: preliminry report. Pin 1989;37: Bruer E, Wtnbe S. New developments in the ssessment of pin in cncer ptients. Support Cre Cncer 1994;2: Bruer E, Schoeller T, Wenk R, McEchern T, Mrcelino S, Surez-Almzor M, Hnson J. A prospective multi-center ssessment of the Edmonton Stging System for cncer pin. J Pin Symptom Mnge 1995;10: Finsinger R, Schoeller T, Bruer E. Methdone in the mngement of cncer pin: review. Pin 1993;52: Bruer E, Pereir J, Wtnbe S, Belzile M, Kuehn N, Hnson J. Opioid rottion in ptients with cncer pin: retrospective comprison of dose rtios between methdone, hydromorphone nd morphine. Cncer 1996;78: Bruer E, Ripmonti, C. Adjuvnts to opioid nlgesics. In: Ptt R, ed. Cncer pin. Phildelphi: J. B. Lippincott, 1993: Mrtin LA, Hgen NA. Neuropthic pin in cncer ptients: mechnisms, syndromes nd clinicl controversies. J Pin Symptom Mnge 1997;14: Wtnbe S, Bruer E. Corticosteroids s djuvnt nlgesics. J Pin Symptom Mnge 1994;9: Ahmedzi S, Alln E, Fllon M, et l. The TTSfentnyl multicentre study group: trnsderml fentnyl in cncer pin. J Drug Dev 1994;6: Ahmedzi S, Brooks D. Trnsderml fentnyl versus sustined-relese orl morphine in cncer pin: preference, efficcy, nd qulity of life. The TTS-Fentnyl Comprtive Tril Group. J Pin Symptom Mnge 1997;13: Donner B, Zenz M, Tryb M, Strumpf M. Direct

7 Vol. 18 No. 4 October 1999 Lxtive Use nd Opioid Rottion to Methdone 309 conversion from orl morphine to trnsderml fentnyl: multicentre study in ptients with cncer pin. Pin 1996;64: Donner B, Zenz M, Strumpf M. Long-term tretment of cncer pin with trnsderml fentnyl. J Pin Symptom Mnge 1998;15: Megens AAHP, Artois K, Vermeire J, Meert T, Awouters FHL. Comprison of the nlgesic nd intestinl effects of fentnyl nd morphine in rts. J Pin Symptom Mnge 1998;15: Zenz M, Donner B, Strumpf M. Withdrwl symptoms during therpy with trnsderml fentnyl (fentnyl TTS)? J Pin Symptom Mnge 1994;9: Higgs CMB, Vell-Brinct J. Withdrwl with trnsderml fentnyl [letter]. J Pin Symptom Mnge 1995;10: Brooks DJ, Trvers M, Wooding S, Ahmedzi S. Incidence of morphine withdrwl syndrome on chnging between two mu gonists. In: Pin mechnisms nd mngement. A scientific meeting in honor of Smpson Lipton, September , Liverpool. Liverpool: Pin Reserch Institute, 1995: Hunt R. Trnsderml fentnyl nd the opioid withdrwl syndrome [letter]. Pllit Med 1996;10: Dvies AN. Trnsderml fentnyl nd the opioid withdrwl syndrome [letter]. Pllit Med 1996;10: Dole VP, Kreek MJ. Methdone plsm level: sustined by reservoir of drug in the tissue. Proc Ntl Acd USA 1973;70: Mercdnte S, Spio M, Serrett R. Tretment of pin in chronic bowel subobstruction with selfdministrtion of methdone. Support Cre Cncer 1997;5: Mnfredi PL, Borsook D, Chndler SW, Pyne R. Intrvenous methdone for cncer pin unrelieved by morphine nd hydromorphone: clinicl observtions. Pin 1997;70: Fitzgibbon DR, Redy LB. Intrvenous highdose methdone dministered by ptient controlled nlgesi nd continuous infusion for the tretment of cncer pin refrctory to high-dose morphine. Pin 1997;73: