Vol. 16 No. 5 Novemer 1998 Journl of Pin nd Symptom Mngement 317 Originl Article Ineffectiveness of Dextromethorphn in Cncer Pin Sestino Mercdnte, MD, Alessndr Csuccio, MD, nd Giuseppe Genovese, MD Pin Relief nd Pllitive Cre, (S.M., G.G.), SAMOT, Plermo, Itly; Deprtment of Anesthesi nd Intensive Cre, (S.M.), Buccheri L Ferl Fteenefrtelli Hospitl, Plermo, Itly; Deprtment of Hygiene nd Microiology, (A.C.), University of Plermo, Plermo, Itly Astrct Experimentl studies hve indicted tht N-methyl-D-sprtte (NMDA) receptor ntgonists my e effective nlgesics in wide vriety of chronic pin sttes. The mechnism is presumed to e relted to decresed firing of dorsl horn neurons fter constnt repeted C-fier stimultion. Dextromethorphn (DM), potent NMDA ntgonist with good sfety profile, my e promising gent for the tretment of persistent pin. An open-lel rndomized tril ws designed to exmine the effects of comining DM with NSAIDs, dextropropoxyphene, or morphine in cncer ptients with pin. Ptients who required chnge in the step of the World Helth Orgniztion s (WHO) nlgesic ldder ecuse of pin level of 4 or more on numericl pin scle were rndomly llocted to receive DM 30 mg three times dy (30 ptients) or conventionl tretment (30 ptients). There were 20 ptients rndomized for ech step of the nlgesic ldder. Pin mechnisms, pin intensity (numericl 0 10 scle), symptoms more frequently present in dvnced cncer ptients or ssocited with opioid therpy (grded on 0 3 scle not t ll, slight, lot, wful), opioid escltion index, dys on opioid tretment, nd dverse effects were recorded. After 2 dys 75%, 80%, nd 100% of ptients treted with DM in steps 1,2, nd 3, respectively, required conventionl tretment, ecuse dequte pin relief hd not een chieved (pin scle 4). Filure of this tretment ws eqully oserved in neuropthic pin or nociceptive pin syndromes. Four ptients treted with DM who did not require the conventionl tretment immeditely did require this chnge fter some dys, due to poor pin control. A highly significnt reduction in pin ws oserved in ptients directly treted with the conventionl tretment in ll the three steps of the nlgesic ldder. No significnt nlgesic effects could e found when DM t this dose ws comined with NSAIDs, dextropropoxyphene, or morphine. J Pin Symptom Mnge 1998; 16:317 322. U.S. Cncer Pin Relief Committee, 1998. Key Words Cncer pin, dextromethorphn, WHO method, neuropthic pin Introduction Currently, nonsteroidl nti-inflmmtory drugs (NSAIDs) nd opioids sequentilly dmin- Address reprint requests to: Sestino Mercdnte, MD, Pin Relief nd Pllitive Cre, SAMOT, Vi Liertà 191, 9143 Plermo, Itly. Accepted for puliction: Mrch 25, 1998. istered ccording to the nlgesic ldder proposed y the World Helth Orgniztion (WHO), remin the minsty of cncer pin mngement. 1 However, NSAIDs nd opioids re well known to hve limits ecuse of their side effects. The use of nlgesic drugs with different mechnisms of ction my permit the use of lower dosges nd could e useful in this regrd. U.S. Cncer Pin Relief Committee, 1998 0885-3924/98/$ see front mtter Pulished y Elsevier, New York, New York PII S0885-3924(98)00096-7
318 Mercdnte et l. Vol. 16 No. 5 Novemer 1998 Recent insights into mechnisms of chronic pin hve indicted the involvement of centrl nervous system excittory mino cid receptors. Constnt C-fier stimultion following tissue injury cuses frequency-dependent increse in the firing of dorsl horn neurons, which hs een termed wind-up. The tonic input due to repeted stimultion of the peripherl nerves, such s my occur in cncer ptients with tissue injury, my led to centrl sensitiztion of dorsl horn neurons. Centrl sensitiztion results in incresed spontneous ctivity, incresed responsiveness to peripherl stimuli, nd expnded receptive fields of dorsl horn nociceptive neurons. Pin induced y nerve injury, which is lso ssocited with centrl sensitiztion, hs een shown to shift the dose response curve of opioids to the right. 2 N-methyl-D-sprtte (NMDA) is n gonist t the excittory mino cid receptor. Experimentl studies hve indicted tht NMDA receptor ntgonists my e effective nlgesics in wide vriety of chronic pin sttes. NMDA lockde hs een found to reduce the incresed firing of dorsl horn neurons fter constnt C-fier stimultion. 3,4 Low doses of opioids nd NMDA ntgonists hve een reported to produce profound depression of neuronl responses nd to restore opioid responsiveness in niml models of neuropthic pin. 5 Of interest, some opioids, such s ketoemidone, methdone, nd meperidine seem to hve dditionl nonopioid nlgesic effects due to NMDA locking effect. 6,7 Dextromethorphn (DM) is potent NMDA ntgonist. It hs strong sfety nd efficcy profile s n ntitussive. 8 As it does not pper to produce psychomimetic side effects, s ketmine, nother NMDA receptor ntgonist does, it my e promising gent for the tretment of persistent pin. 9 DM hs een shown to selectively reduce temporl summtion of second pin in norml volunteer humn sujects t orl doses of 30 45 mg. 10 It lso hs een shown to gretly potentite the nlgesic ctivity of nti-inflmmtory drugs (NSAIDs) nd increse the pek effect over NSAIDs lone. 11 Wheres NSAIDs hve their min phrmcologic effect in the periphery, where inflmmtion nd nociceptor input nd sensitiztion originte, NMDA ntgonists prevent or reverse the centrl sensitiztion induced y the excittory mino cid ctivtion. Thus, centrl interction etween NSAIDs nd NMDA receptor ntgonists in modulting centrl sensitiztion my lso occur. 11 DM lso fcilittes morphine nlgesi 12 nd similrly potentites nlgesi produced y orlly dministered codeine, oxycodone, nd hydrocodone. 11 When given in comintion with morphine, DM ttenuted nd reversed tolernce to the ntinociceptive effects of morphine. Moreover, DM incresed the ntinociceptive effects of morphine with single dministrtion of morphine DM (1:1) comintion. 12 A comintion of n opioid nd n NMDA ntgonist produces profound depression of neuronl responses including wind-up nd restores opioid sensitivity in experimentl models of neuropthic pin 5,13 Incresed ntinociceptive effects of morphine were shown when low doses of morphine were comined with DM. 12 These dt suggest tht the comintion of DM with NSAIDs or opioids my represent useful pproch to improve the mngement of cncer pin. This study exmined the effects of comining DM with NSAIDs, dextropropoxyphene, nd morphine in cncer ptients with pin t the time of pssing to the next step of the WHO nlgesic ldder. The generl hypothesis tested ws tht these comintions would result in etter nlgesi. Methods The study ws crried out from Novemer 1994 to Ferury 1996 in home pllitive cre setting. Institutionl pprovl ws otined. Ptients with coexisting liver or renl disese, or encephlopthy were excluded. We included only those ptients who required chnge in the step of the nlgesic ldder ecuse of pin level of 4 or more on the numericl pin scle nd who greed with the study protocol. Ptients were rndomly llocted, y using list of rndom numers, to receive DM 30 mg three times dy (D-tretment) or the conventionl tretment (C-tretment, see elow). No other drugs different from those previously dministered were used during the period of study. Ptients previously treted with NSAIDs requiring the next step of the nlgesic ldder (opioids for moderte pin) were included in group 1 (20 ptients). Group 2 (20 ptients) included ptients who hd lredy een
Vol. 16 No. 5 Novemer 1998 Ineffectiveness of Dextromethorphn 319 treted with opioids for moderte pin nd needed strong opioids. Group 3 included ptients on morphine therpy who required n increse in dose (20 ptients). Thirty ptients, 10 ptients in ech group respectively, received 30 mg of DM three times dy for 2 dys (D-tretment). In cse of poor pin control (pin scle 4), ptients were dministered conventionl tretment (DC-tretment) consisting of dextropropoxyphene 60 mg 4 times dy for group 1; morphine 30 60 mg dy, depending on ge, for group 2; nd n increse of 30 40% of the morphine dose for group 3. DM ws continued if ptients greed. Thirty ptients (C-tretment), 10 ptients in ech group respectively, did not receive DM nd were directly treted with the conventionl tretment. Nonopioid drugs were continued if not contrindicted, t the sme dosge ccording to stndrd protocol (minly diclofenc 100 mg y orl route or 75 mg y intrmusculr route twice dy). Other drugs previously dministered, such s djuvnts, were continued during the study s well s the ones generlly dministered in pllitive cre to control symptoms due to the illness or tretment. No ptient received nticncer therpy during the course of the study. All the ptients were treted t home y tem consisting of doctors nd nurses experienced in pllitive cre. All ptients received 2 3 home visits week until deth. The following dt were regulrly recorded efore strting the protocol (T0), nd t 2-dys intervls fter strting DM (D-tretment) or the conventionl tretment (C-tretment) (T1). The dt were recorded 2 dys fter strting the conventionl tretment in those ptients who filed D-tretment (DC-tretment) (T2): pin mechnisms, on the sis of the clinicl history, ntomicl site of primry tumor nd distnt metstses, physicl exmintion, nd the most recent imging studies, when ville; ptient-rted pin intensity (numericl 0 10 scle); symptoms more frequently present in dvnced cncer ptients or ssocited with opioid therpy, grded on ptient-rted scle from 0 to 3 (not t ll, slight, lot, wful); opioid escltion index, clculted s the men increse of opioid dosge in mg from the opioid strting dose (OSD), using the following formul: OMD OSD/dys, where OMD is the mximum opioid dose, expressed s equinlgesic dose of orl morphine in mg; 1 dys on opioid tretment; dverse effects. Sttisticl nlysis ws performed y Student s t test for pired dt nd chi-squre test when required. Sttisticl significnce ws tken s P 0.05. Results A totl of 58 ptients completed the study. Two ptients on D-tretment in group 1 were excluded ecuse of protocol violtion. There were no significnt differences etween D- nd C-tretment ptients in the three groups in terms of ge, gender, presence of neuropthic pin, nd primry cncer (Tle 1). Bseline pin nd symptom intensity were not significntly different. No sttisticl differences in opioid escltion index nd the men pin scores until deth were found (Tle 2). These dt underline tht ptients nd their pin syndromes were eqully responsive to opioids. The numer of ptients presenting new symptom or n increse in symptom intensity with D-tretment, DC-tretment, or C-tretment re shown in Tles 3 5. Other symptoms were not included in the tles ecuse Tle 1 Age, Gender, Presence of Neuropthic Pin, nd Primry Cncer in the Three Study Groups Group 1 Group 2 Group 3 D-DC C D-DC C D-DC C Age (men) 62.5 62.7 63.4 63.7 63.9 60.9 Sex (M/F) 5/5 6/4 6/4 5/5 5/5 5/5 Pin mechnisms somtic 6 7 7 5 5 7 viscerl 3 6 6 4 6 3 neuropthic 3 2 4 3 4 3 Primry cncer lung 2 2 1 3 2 3 rest 1 2 2 1 1 3 pncres 1 1 1 eso-stomch 1 1 1 1 liver 1 1 1 1 1 colon 1 1 1 urogenitl 2 4 3 1 2 2 hed neck 1 1 1 melnom 1 thyroid 1 mesotheliom 1 Arevitions: D-DC DM-tretment nd then conventionl tretment; C conventionl tretment.
320 Mercdnte et l. Vol. 16 No. 5 Novemer 1998 Tle 2 Opioid Escltion Index (OEI), Pin Intensity (10-Point Numeric Scle) During Tretment, nd Dys on Opioids OEI Pin 0-dys Group 1 D-DC 1.3 3.5 66 (29 117) C 1.4 3.5 62 (18 121) Group 2 D-DC 1.5 3.5 65 (14 189) C 1.4 3.6 48 (22 93) Group 3 D-DC 1.2 3.4 48 (13 108) C 2.3 3.2 63 (15 141) Results re expressed s men, nd, in the cse of 0-dys, men (rnge). they were not relevnt. Symptom intensity in the different groups is reported in Tle 6. Constiption nd dry mouth were the symptoms with highest intensity, especilly in group 3 (ptients lredy on morphine). After 2 dys, 75%, 80%, nd 100% of ptients with D-tretment in groups 1, 2, nd 3, respectively, required conventionl tretment (DC), ecuse dequte pin relief hd not een chieved (pin rted 4). Filure of this tretment ws eqully oserved oth in neuropthic pin or nociceptive pin syndromes. The four ptients with D-tretment, who hd previously mintined pin of 4 or less, required the conventionl tretment fter 12 nd 7 dys (group 1) nd 2 nd 4 dys (group 2), respectively, due to poor pin control. Ptients who greed to continue DM during the conventionl tretment (DC) (2,1, nd 2 ptients in groups 1, 2, nd 3, respectively) presented similr opioid escltion index nd men pin scores. Tle 4 Numer of Ptients in Group 2 Presenting New Symptom or n Increse in Symptom Intensity with D (DM-tretment), DC (DM-tretment nd then Conventionl Tretment), nd C (Conventionl Tretment) Group 2 D (10) DC (8) C (10) Nuse-Vomiting 2 4 Dry mouth 3 7 Constiption 1 1 Drowsiness 1 4 6 Confusion 1 2 Pin score 0.3(6%) 1.5(30%) 1.8(38%) The sl vlue for DC is D (tht is, vlue otined fter the previous tretment with DM). The vlue of pin score is considered s decrese ( ) or n increse ( ) of the previous vlue. No differences in pin were oserved fter D-tretment in ll the groups. However, reduction in pin ws oserved in ptients who hd filed D-tretment nd then received the conventionl tretment (DC-tretment) in groups 2 nd 3, lthough this did not ttin significnce in group 1. A highly significnt reduction in pin ws oserved in ptients directly treted with the conventionl tretment (C-tretment) in ll the three groups (see Tle 6). In Tle 7 the drugs previously dministered in the different groups re listed. No relevnt differences were oserved. Discussion The rtionle for this study ws the ssumption tht DM would reinforce the nlgesic effects of NSAIDs nd opioids ecuse of its Tle 3 Numer of Ptients in Group 1 Presenting New Symptom or n Increse in Symptom Intensity with D (DM-tretment), DC (DM-tretment nd then Conventionl Tretment), nd C (Conventionl Tretment) Group 1 D (10) DC (6) C (10) Nuse Vomiting 1 2 1 Dry mouth 4 3 Constiption 3 Drowsiness 3 1 5 Confusion 2 Pin score 0 0.8(17%) 1.3(28%) The sl vlue for DC is D (tht is, vlue otined fter the previous tretment with DM). The vlue of pin score is considered s decrese ( ) or n increse ( ) of the previous vlue. Tle 5 Numer of Ptients in Group 3 Presenting New Symptom or n Increse in Symptom Intensity with D (DM-tretment), DC (DM-tretment nd Then Conventionl Tretment), C (Conventionl Tretment) Group 3 D (10) DC (10) C (10) Nuse-Vomiting 3 1 1 Dry mouth 1 Constiption Drowsiness 2 3 Confusion 1 Pin score 0.6(13%) 1.9(38%) 1.5(31%) The sl vlue for DC is D (tht is, vlue otined fter the previous tretment with DM). The vlue of pin score is considered s decrese ( ) or n increse ( ) of the previous vlue.
Vol. 16 No. 5 Novemer 1998 Ineffectiveness of Dextromethorphn 321 Tle 6 Symptom Intensity (Expressed s Men) nd Pin Scores in the Three Groups t T0 (Bsl Vlue for D nd C), T1 (Bsl Vlue for DC) nd T2 N-V X C D S Men SE 95% CI Group 1 D DC T0 0.3 0 0 0 0.37 4.5 0.19 4.17 5.03 T1 0.5 0 0 0.25 0.5 4.5 0.38 3.76 5.24 T2 0.8 0.8 0 0.6 0.6 3.7 0.56 2.60 4.80 C T0 0.4 0.2 0.2 0.1 0.7 4.6 0.22 4.17 65.03 T1 0.5 0.5 0.3 0.7 0.9 3.3 0.30 2.71 3.89 d Group 2 D DC T0 0.2 0.4 0 0 1.1 4.6 0.26 4.09 5.11 T1 0.2 0.4 0 0.1 1.1 4.9 0.43 4.09 7.74 T2 0.6 0.87 0.25 0.5 1.25 3.4 0.46 2.50 4.30 C T1 0.4 0.5 0.1 0.1 0.8 4.7 0.21 4-29 5.11 T2 0.8 1.2 0.2 0.7 0.9 2.9 0.31 2.29 3.51 e Group 3 D DC T0 0.4 1 0.1 0.4 1.5 4.4 0.16 4.09 4.71 T1 0.7 1 0.1 0.4 1.5 5 0.26 4.49 5.51 T2 0.7 1.1 0.2 0.6 1.5 3.1 0.23 2.65 3.55 e C T0 0.2 1 0 0.5 1.3 4.8 0.79 4.31 5.29 T1 0.3 1 0 0.8 1.4 3.3 0.42 2.48 4.12 c Arevitions: N-V nuse nd vomiting, X dry mouth, C confusion, D drowsiness, S constiption, DM DM-tretment; DC DM tretment nd then some conventionl tretment; C conventionl tretment. The sl vlue for DC is D (tht is, vlue otined fter the previous tretment with DM). P 0.05, c P 0.01, d P 0.005, e P 0.0005 when compred to the sl vlues. NMDA ntgonist ctivity nd the ility to reduce centrl sensitiztion. 10 12,14 DM ws dministered efore proceeding with the next steps of the nlgesic ldder proposed y the WHO to ddress uncontrolled pin: NSAIDs, opioids used for moderte pin (dextropropoxyphene), nd strong opioids (morphine). These effects were compred t ech step with those produced y the conventionl tretment in similr ptients nd in the sme ptients if DM hd filed fter 2 dys. The results indicte n sence of relevnt nlgesic effects of DM in cncer pin t the doses used in this study, either with nociceptive or neuropthic mechnisms. A cler difference ws oserved when compred with the conventionl tretment in terms of nlgesi, lthough no significnt influence on the occurrence of dverse effects ws oserved. DM did not induce relevnt dverse effects on short-term sis. Potentilly, higher doses of DM for prolonged periods would hve more nlgesic effects or would produce decrese in opioid tolernce, s experimentlly reported. 14 We therefore cnnot exclude n nlgesic effect using different dosges, durtion of tretment, pproches, or route of dministrtion. The sme rnge of doses used in this study hs een shown to e ineffective for the tretment of neuropthic pin nd to induce relevnt dverse effects. 15 Poor nlgesic effects were lso oserved y others. 16 Other studies indicte tht nlgesi cn e enhnced when using morphine equivlent-dm rtio of 1:1, s dministered to ptients in group 3. 12 The DM-medited effects seem to depend on the rtio of morphine/dm rther thn on the solute DM mount. Incresing doses of DM would require incresing doses of morphine. 12 Although DM is le to ct s n NMDA receptor ntgonist, sufficient plsm, cere- Tle 7 Drugs Previously Used efore Strting the Study Protocol (Numer of Ptients) Group 1 Group 2 Group 3 D-DC C D-DC C D-DC C Diclofenc 5 4 4 3 2 2 Ketorolc 1 2 1 4 1 3 Iuprofen 1 1 1 Dypirone 1 Amitriptyline 3 2 2 Crmzepine 1 1 2 Rnitidine 3 4 3 5 5 5 Niztidine 1 Omeprzol 1 Metocloprmide 1 3 2 3 4 2 Hloperidol 2 1 2 3 2 Steroids 1 2 2 3 Lxtives 1 4 2 8 7 Drugs were continued during the study.
322 Mercdnte et l. Vol. 16 No. 5 Novemer 1998 rospinl fluid, or tissue concentrtions must e chieved to hve this effect. It is uncertin tht this occurred. The incresed pin intensity reported with DM in previous studies 15 ws oserved in ptients no longer responsive to NSAIDs or opioids for moderte pin, lthough this effect my e ttriutle to the progression of disese, rther thn to n ntinlgesic effect. The regulr dministrtion of the susequent step of the nlgesic ldder ws followed y n dequte pin relief in most cses. Ptients who continued on DM tretment hd no sustined enefits, which hs lso een reported in ptients with chronic neuropthic pin. 15 These oservtions re the first on the use of DM in cncer pin. Despite the potentilly useful role derived from experimentl work, no clinicl dvntge could e found when DM, t doses of 90 mg dily, ws comined with the drugs of the nlgesic ldder. This initil experience ws open-lel, y ethicl necessity nd clinicl setting, nd designed to test efficcy nd side effects of DM. Although the nlgesic efficcy nd other outcomes my e compromised y plceo effect, these preliminry results my e useful to design other prospective doule-lind studies on DM in cncer pin using higher doses or longer tretment. Acknowledgment We wish to thnk Mrs. Kti Messin Clderone for her help with the English revision. References 1. Hnks GW, Justins DM. Cncer pin: mngement. Lncet 1992;339:1031 1036. 2. Jdd AR, Crroll D, Glynn CJ, Moore RA, Mc- Quy HJ. Morphine responsiveness of chronic pin: doule-lind rndomised crossover study with ptient controlled nlgesi. Lncet 1992;339: 1367 1371. 3. Dickenson AH, Sullivn AF. Differentil effects of excittory mino cid ntgonists on dorsl horn nociceptive neurones in the rt. Brin Res 1990;506: 31 39. 4. Coderre TJ, Ktz J, Vccrino AL, Melzck R. Contriution of centrl neuroplsticity to pthologicl pin: review of clinicl nd experimentl evidence. Pin 1993;52:259 285. 5. Ymmoto T, Yksh TL. Studies on the spinl interction of morphine nd NMDA ntgonist MK- 801 on the hyperesthesi oserved in rt model of scitic mononeuropthy. Neurosci Lett 1992;135: 67 70. 6. Eert B, Andersen S, Krogsgrd-Lrsen P. Ketoemidone, methdone nd pethidine re non-competitive NMDA ntgonists in the rt cortex nd spinl cord. Neurosci Lett 1995;187:165 168. 7. Andersen S, Dickenson AH, Kohn M, Reeve A, Rhmn W, Eert B. The opioid ketoemidone hs NMDA locking effect. Pin 1996;67:369 374. 8. Bem JL, Peck R. Dextromethorphn: n overview of sfety issues. Drug Sfety 1992;7:190 199. 9. Ren K. Wind-up nd the NMDA receptor: from niml studies to humns. Pin 1994;59:157 158. 10. Price DD, Mo J, Frenk H, Myer DJ. The N-methyl-D-sprtte receptor ntgonist dextromethorphn selectively reduces temporl summtion of second pin in mn. Pin 1994;59:165 174. 11. Price DD, Mo J, Lu J, Cuso FS, Frenk H, Myer DJ. Effects of the comined orl dministrtion of NSAIDs nd dextromethorphn on ehviorl symptoms indictive of rthritic pin in rts. Pin 1996;68:119 127. 12. Mo J, Price DD, Cruso FS, Myer D. Orl dministrtion of dextromethorphn prevents the development of morphine tolernce nd dependence in rts. Pin 1996;67:361 368. 13. Chpmn V, Dickenson AH. The comintion of NMDA ntgonism nd morphine produces profound ntinociception in the rt dorsl horn. Brin Res 1992;573: 321 323. 14. Mnning BH, Mo J, Frenk H, Price DD, Myer DJ. Continuous co-dministrtion of dextromethorphn or MK-801 with morphine: ttenution of morphine dependence nd nloxone-reversile ttenution of morphine tolernce. Pin 1996;67:79 88. 15. McQuy HJ, Crroll D, Jdd AR, Glynn CJ, Jck T, Moore RA, Wiffen PJ. Dextromethorphn for the tretment of neuropthic pin: doule-lind rndomised controlled crossover tril with integrl n-of-1 design. Pin 1994;59:127 133. 16. Kuppil T, Gronroos M, Pertovr A. An ttempt to ttenute experimentl pin in humns y dextromethorphn, n NMDA receptor ntgonist. Phrmcol Biochem Behv 1995;52:641 644.