Oxycodone pentru dureri asociate cancerului

Meta-analysis of Randomized Controlled Trials Meta analiz pentru studii clinice randomizate SUMAR

Pentru a evalua eficacitatea i tolerabilitatea oxycodonului n dureri asociate cancerului, am desfurat o recenzie sistematic a studiilor clinice randomizate. Pentru meta analiz au fost potrivite patru studii, care compar oxycodone administrat oral cu morfina oral (n=3) sau cu hidromorfon oral (n=1). Diferenele medii standardizate n scorurile durerii, care compar oxycodone cu grupurile controlate au fost puse de acord prin folosirea modelelor cu efecte ntmpltoare. n ansamblu, nu exist dovezi privind faptul c scorurile medii ale durerii au fost diferite n cazul oxycodonului fa de medicamentele de control (diferen medie standardizat, 0,04; 95% interval de ncredere [CI], -0,29 pn la 0.36; P = .8; I2 = 62%). n analiza meta-regresiv, scorurile durerii au fost mai ridicate pentru oxycodone n comparaie cu morfina (0.20; 95% CI, 0.04 la 0.44) i mai sczute n comparaie cu hidromorfonul (0.36; 95% CI, 0.71 la 0.00), dei mrimea acestor efecte era mic. Eficacitatea i tolerabilitatea oxycodone-ului sunt similare cu cele ale morfinei, ceea ce susine ideea folosirii lui ca opioid pentru durerile asociate cancerului.
INTRODUCERE

Aproximativ jumtate dintre pacieni cu cancer avansat sufer de dureri moderate spre severe. Opioidele reprezint suportul tratamentului, iar morfina este opioidul ales. Atunci cnd morfina este folosit corect, aproximativ 80% dintre pacieni vor ajunge la o uurare corespunztoare a durerii. Cu toate acestea, aproximativ 20% nu vor simi acest lucru i vor trebui s schimbe pe un opioid alternativ. Pentru o parte din aceti pacieni, aceasta se ntmpl deoarece exist efecte adverse nepermise asociate cu morfina. Oxycodonul este un derivat
Oxycodone is a semisynthetic derivative of morphine. It has been in clinical use since 1917,6 but patterns of use have differed worldwide, perhaps reflecting a lack of clinical studies investigating its efficacy. Historically, it was most commonly used in the United States as an opioid for mild to moderate pain in low-dose combinations with acetaminophen (paracetamol) or aspirin. In such preparations, however, its use was limited, as its dose could not be increased because of potential acetaminophen or aspirin toxicity. It was also used for moderate to severe pain in Finland (mostly by parenteral administration). Studies conducted since 1990 have suggested that, when used in single-entity formulations and with dose titration, oxycodone is as effective as morphine. 7-8 The 1996 European Association for Palliative Care guidelines recommended oxycodone as an alternative to morphine.3 Although there has been speculation that oxycodone may have a better adverse effect profile compared with morphine, 9 there are limited data on cancer-related pain. Since 1996, oxycodone has been relaunched in different formulations and dose strengths and in modified-release preparations, increasing its potential for use in chronic cancer pain. The success of this relaunch is indicated by

English Department of Health statistics,10 which show that the percentage of annual growth in items of oxycodone prescribed from 2002 to 2003 was 43%, compared with 8% for all opioid analgesics. Annual consumption of oxycodone has increased 42-fold in the United Kingdom and 3-fold in the United States from 1999 to 200311 (Figure 1). We conducted a systematic review of the available evidence to determine the efficacy and tolerability of oxycodone for cancer-related pain.

Figure 1. Consumption of oxycodone in the United Kingdom and the United States from 1999 to 2003. Data from the International Narcotics Control Board.11

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Jump to Section METHODS Top

Introduction Methods Results Comment Author information References

ELIGIBILITY We included randomized controlled trials comparing oxycodone with placebo or an active analgesic drug in patients with cancerrelated pain. All routes of drug administration and all formulations of oxycodone were considered. Studies of combination oxycodone preparations (eg,

oxycodone and acetaminophen) were excluded. SEARCH STRATEGY We searched the following electronic databases using a detailed search strategy for each: Cochrane Pain, Palliative and Supportive Care Register 2002; Cochrane Controlled Trials Register 2002: Cochrane Library current issue; MEDLINE (1966 to May 2002); EMBASE (1980 to May 2002); CancerLit (1960 to May 2002); CINAHL (1982 to May 2002); dissertation abstracts (2002); and SIGLE (2002). We searched reference lists of retrieved articles and other relevant literature such as pain or opioid reviews. We wrote to the manufacturers of oxycodone preparations (Napp Pharmaceuticals, Cambridge, England, and Purdue Pharma, Stamford, Conn), known oxycodone investigators, and subscribers of Palliative Medicine and selected pain journals with a request for data from unpublished trials or information about other trials we had not identified. The search strategy was repeated in April

2005, with no new studies identified. Search terms are listed in Figure 2.

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DATA EXTRACTION The full-text versions of potentially eligible articles were obtained and independently assessed by 2 of the investigators (C.M.R. and A.N.D.). We identified duplicate publications by reviewing study name, authors, location, study population, dates, and study design and by confirming with the study authors and Napp Pharmaceuticals (the manufacturers of oxycodone in

England) that each of the included reports were indeed separate studies. We identified replication of efficacy data from trials by Kalso et al12 and Heiskanen et al13 contained within separate articles reporting on the pharmacokinetic outcomes from these studies. Reasons for excluding a trial were recorded. For eligible trials, both investigators independently extracted data from the article using a specifically designed data extraction form. This form recorded the following: publication details, patient population details, nature of pain if described, interventions, outcome measures used, analgesic (efficacy) results, adverse effects, quality-of-life scores, patient preference, withdrawals, and trial quality criteria. We extracted data on reported methods of concealment of allocation14 and the blinding of therapists, patients, and outcome assessors in each trial. ANALIZA DATELOR

Au fost folosite diferite scheme de evaluare pentru a

nregistra scorurile durerii n studiile clinice (Tabelul 1). Am exprimat efectele tratamentului ca diferene medii ponderate standardizate. Pentru studiul de grup paralel, diferena medie ponderat standardizat a fost calculat folosinduse estimatorul Glass i eroarea standard calculat conform ecuaiei 9 a lui Curtin .c.l. Pentru studii ncruciate, diferenele medii ponderate standardizate au fost estimate conform ecuaiei 11 a lui Curtin .c.l. prin divizarea efectului tratamentului de ctre devierea standard a inter- i intra-subiecilor a diferenelor ncruciate. Pentru a estima devierea standard a diferenelor ncruciate, a fost estimat un coeficient de corelaie intra-clas de 0,2 prin folosirea informaiilor de nivel individuale disponibile numai pentru studiile clinice fcute de Heskanen i Kalso. Estimrile varianei mrimii efectului ncruciat au fost mai apoi derivate

prin ecuaia 14 a lui Curtin .c.l. Deoarece studiile clinice au folosit diferite grupuri de control (morfin sau hidromorfon) i pentru c erau dovezi privind eterogenitatea interstudiilor clinice, studiile clinice au fost puse de acord folosind meta analiz cu efecte ntmpltoare. Am analizat scorurile durerii nregistrate n ultima zi pe fiecare medicament studiat pentru a ne asigura c a fost atins o stare de echilibru. Au fost obinute informaii asupra prezenei sau absenei a 16 efecte adverse asociate opioidelor de la autorii fiecrui studiu clinic ncruciat. Am folosit estimarea riscului relativ marginal (OR) descris de Becker i Balatgas pentru a obine estimri ale riscului relativ (ORs) i erorile lor standard pentru studiile clinice ncruciate. Pentru fiecare efect advers, aceste estimri ale riscului relativ au fost combinate cu estimrile riscului relativ corespunztoare, derivate din raportul publicat al studiului clinic al grupului paralel. Statistica I2

a fost folosit pentru a evalua extinderea variaiei inter-studiu n estimri i sursele de eterogenitate au fost explorate folosind meta regresia. Analizele au fost conduse cu ajutorul softwareului statistic Stata, versiunea 8.0 (metaanaliza efectelor durerii) i RevMan, versiunea 4.2.7 (Centrul Nordic Cochrane, Copenhaga, Danemarca) (metaanaliza efectelor adverse).

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REZULTATE

Strategia de cercetare a produs 104 referine, dintre care 6 studii clinice au respectat criteriile de incluziune (Figura 3). Din acestea, 1 era un studiu privind doza unic, care evalua potena analgezicului i durata aciunii oxycodonului intramuscular contra morfinei

intramusculare i a codeinei fosfat. Din cele 5 rapoarte rmase, 3 studii clinice ncruciate au comparat oxycodonul oral cu morfina oral; 1 studiu clinic ncruciat a comparat oxycodonul oral cu hidromorfonul oral, iar un studiu clinic pe grup paralel a comparat oxycodonul oral cu morfina oral. (Tabelul 1).

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Nici unul studiile eligibile nu au raportat informaii ntr-o form potrivit pentru meta-analiz, aa c am contactat autorii sau companiile de medicamente care

au realizat sponsorizarea pentru informaii suplimentare. De asemenea am solicitat informaii suplimentare asupra prezenei sau absenei efectelor adverse examinate n studiile clinice. Informaii despre pacieni individuali au fost obinute pentru studiu de ctre Heiskanen i Kalso. Pentru studiile lui Bruera .c.l., Hagen i Babul i MucciLoRusso .c.l., ne-au fost oferite diferene medii intra-pacieni ale scorurilor durerii (care compar prima i ultima zi de studiu), precum i o estimare a deviaiei standard. Datele analizabile nu au fost disponibile pentru studiile fcute de Kalso i Vainio (care nu au raportat vreo diferen statistic semnificativ n clasificrile scalei analog vizuale ntre grupurile de morfin i oxycodon, ci grea mai mult n cazul morfinei orale), i Beaver .c.l. (care au demonstrat c oxycodonul intramuscular era de 0,68 de ori mai puternic dect morfina intramuscular, dar avea o durat de aciune ceva ai mic). Ca urmare, 4 studii au fost incluse n

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meta-analiz.
CALITATEA METODOLOGIC A STUDIILOR INCLUSE

Numai un studiu clinic (Heiskanen i Kalso) a relatat despre metoda de ascundere a distribuirii tratamentului (codul de randomizare a fost pstrat de ctre farmacistul spitalului), dei informaiile despre cazul n care randomizarea restricionat a fost sau nu folosit n generarea secvenei de alocare nu au fost disponibile n raportul studiului clinic. (Tabelul 2). Toate studiile clinice au folosit tablete placebo potrivite pentru a orbi pacientul i medicul. Nici un studiu nu a indicat
All of the trials used matched placebo tablets to blind the patient and clinician. No studies indicated whether analysis by intention to treat was undertaken. In all included trials, patients who withdrew from the study for any reason were excluded from the final analyses reported herein. The numbers who withdrew from each trial were as follows:

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for Bruera et al,16 32 entered and 9 withdrew; for Hagen and Babul,17 44 entered and 13 withdrew; for Heiskanen and Kalso,18 45 entered and 18 withdrew; and for MucciLoRusso et al,19 101 entered and 22 withdrew (Table 1). None of the publications reported whether the outcome assessor was blinded to treatment. Each trial reported that patients in both treatment groups had their opioid doses titrated in a similar manner until stable doses were obtained. The trials were of short duration, lasting from 10 to 20 days.

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SCORURILE INTENSITII DURERII

n analizele centralizate, nu am descoperit nici o dovad c au fost diferene ntre scorurile medii ale durerii ale oxycodonului i ale

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grupurilor de control (diferene medii ntre scorurile standardizate ale durerii, 0.04; 95% intervalul de ncredere [CI], 0.29 pn la 0.36; P = .8) (Figura 4). Au existat dovezi privind eterogenitatea ntre estimrile studiilor (I2 =62%; eterogenitate P = ,05). Diferena standardizat centralizat n scorurile durerii pentru 3 studii care au comparat oxycodonul cu morfina a fost de 0,20 (95% CI, 0.04 pn la 0.44; I2 = 0%), iar diferena standardizat pentru studiul care a comparat oxycodonul cu hidromorfonul a fost 0.36 (95% CI, 0.71 pn la 0.00; pentru diferene n estimrile efectelor, P = .1). Pe baza diferenelor standardizate centralizate pe care le-am am observat n studiile clinice individuale, am estimat c pentru oxycodonul comparat cu morfina sau hidromorfonul, diferenele standardizate centralizate reprezint numai 2 pn la 3 mm pe o scal analog vizual de 100 mm. Este sugerat faptul c o diferen clinic important reprezint o modificare de 2

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puncte pe o scal a intensitii durerii cu 10 gradaii (echivalent cu o scal analog vizual de 20 mm), ceea ce indic faptul c diferenele standardizate pe care le-am detectat sunt puin probabil aib o importan clinic sau s aib importan pentru pacieni.

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Rezultatele altor efecte descrise n studiile incluse aici sunt detaliate n Tabelul 1. Pe scurt, nu au fost demonstrate diferene n ceea ce privete preferinele pacienilor sau calitatea vieii, dei studiile efectuate de ctre Heskanen i Kalo au sugerat c acceptana pe timp de noapte a morfinei a fost mai bun dect a oxycodonului. Deoarece au fost

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folosite diferite msuri, iar rezultatele nu au fost raportate suficient de detaliat, ele nu au putut fi combinate n meta analize.

EFECTE ADVERSE

Estimrile punctuale pentru estimrile punctului relativ care compa oxycodonul cu grupurile de control au foste de 0.75 (95% CI, 0.51-1.10) pentru grea i 0.72 (95% CI, 0.49-1.06) pentru vom (Tabelul 3.). Exist dovezi nsemnate de eterogenitate n estimrile privind asocierile oxycodonului cu uscciunea mucoasei bucale i somnolen. (I2 = 74% i respective I2 = 71%). Atunci cnd a fost repetat meta analiza folosindu-se numai informaii din studiile clinice care utilizau morfin ca tratament de control, OR-ul centralizat a fost n favoarea oxycodonului pentru uscciunea mucoasei bucale (OR, 0.56; 95% CI, 0.38-0.83) i somnolen (OR, 0.72; 95% CI, 0.471.1). n ansamblu, rata de ntrerupere datorat evenimentelor

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adverse a fost de 13% (29/2229) atunci cnd au fost combinate informaii de la toate studiile; 90% din pacieni au nregistrat efecte adverse asociate opioidelor n fiecare studiu clinic (Tabelul 4). Ratele de ntrerupere datorate efectelor adverse au fost similare n oxycodon i n grupurile de control.

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COMENTARII

Acest studiu este primul despre care cunoatem c prezint dovezile acumulate pentru a arta pe ce se bazeaz prescrierea curent a

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oxycodonului n durerile asociate cancerului. Nu am gsit diferene clinice importante ntre eficacitatea analgezic sau profilul efectelor adverse ale oxycodonului comparativ cu morfina. Dei numai 160 de pacieni au fost inclui n meta analiz, 95% din intervalul de ncredere pentru efectul oxycodonului mpotriva morfinei este ngust i exclude orice diferen important ntre aceste dou medicamente, n ceea ce privete faptul c limita superioar a intervalului de ncredere (diferen standardizat 0,44) este n concordan cu o diferen de numai 6 mm pe o scal analog vizual de 100 mm, iar limita infrioar (-0,04) este n concordan cu o diferen de 0,5 mm. n cazul oxycodonului versus morfina, cifrele echivalente sunt 0 i respectiv 6. Aceste diferene sunt mult mai sczute dect cele despre car ese sugereaz c ar avea importan clinic (o modificare de 20 mm pe o scal analog vizual de 100 mm). Descoperirile noastre subliniaz

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insuficiena informaiilor din acest domeniu, iar rezultatele trebuie s fie interpretate cu grij. Rapoartele studiilor nu ne permit s fim ncreztori n ceea ce privete valabilitii interne a acestor studii clinice. Doar studiul clinic al lui Heiskanen i Kalso a raportat o ncercare de a ascunde administrarea tratamentului, afirmnd c farmacistul spitalului a ascuns codurile. Aceasta nu garanteaz n mod obligatoriu c ascunderea administrrii a avut succes n prevenirea predispoziiilor, deoarece majoritatea proceselor de ascundere pot fi n mod potenial corupte i nici o ncercare de a evalua dac aceast corupere a fost cu adevrat evitat ( de exemplu folosind metodele lui Berger i Exner) nu a fost raportat n nici unul din aceste studii. Ascunderea inadecvat sau neclar a administrrii tratamentului este asociat cu exagerarea efectelor tratamentului i de aceea este improbabil s explicm absena diferenelor clinice importante ntre

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oxycodon i grupul de control, descoperite n meta analiz. n fiecare dintre studiile incluse, pacienii care s-au retras din varii motive nu au fost inclui n analizele finale care comparau scorurile durerii dintre oxycodon i grupurile de control (Tabelul 1), ceea ce a avut ca rezultat posibil eroarea sistematic de uzur, ceea ce ulterior ar putea s amenine validitatea studiilor individuale. Cu toate acestea, deoarece ratele de ntrerupere, ca urmare a evenimentelor adverse, erau similare pentru oxycodon i grupurile de control n toate studiile, pare improbabil c potenialul pentru eroarea sistematic de uzur s explice rezultatele meta analizei noastre. Procentul din pacienii care au ncercat efecte adverse
The percentage of patients experiencing adverse effects and discontinuing treatment due to adverse events was considerable and in line with discontinuation rates from other studies of opioids in cancer and

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noncancer populations.31-33 The prevalence of adverse effects was higher in studies that directly questioned patients about adverse effects compared with those that relied on selfreporting. Because the presence of adverse effects is one of the reasons patients are unwilling to continue or increase doses of medication for pain relief,34 these findings reemphasize the need for active questioning about and aggressive management of opioid-related adverse effects. However, the short duration of these studies also meant that useful data about long-term adverse events such as aberrant drugseeking behavior were not obtained. Although we would not have expected aberrant drugseeking behavior to be a significant problem, as this adverse event appears to be rare in the cancer population,35 evidence from trials might help to dispel the fear of addiction that often hampers good pain control.34 The small number of studies retrieved and the short duration of the studies are

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perhaps a reflection of the difficulties of conducting clinical trials in this group of patients.36-37 High attrition rates due to worsening of the underlying disease or intercurrent illness mean that investigators try to minimize losses to follow-up by designing trials of short duration. Although this approach can provide robust short-term data, it means that results on longer-term efficacy or rates of adverse effects are often not available. Short-term data on comparative effectiveness and adverse events, however, provide important information for clinicians managing cancer pain, to inform patients of the likelihood of beneficial and immediate adverse effects and to reinforce the need for appropriate management of these early adverse effects so that adequate dose titration can be achieved and satisfactory pain relief obtained. The studies recruited outpatients from general cancer or palliative care patient populations, with mixed types of pain from a variety

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of cancers. Where reported, the patients were treated as outpatients, although daily contact was made. It seems likely that the patient population in the trials is representative of patients with cancerrelated pain seen in usual practice (Table 1). It is unclear whether these results are of relevance to patients with chronic noncancer pain, which represents a larger group of patients for whom opioids are considered. Previous systematic reviews32, 38 have examined the efficacy of opioids in various types of noncancer pain, but only 1 review33 has attempted to compare relative efficacies of different opioids. These reviews have confirmed the efficacy of opioids in a variety of chronic pain conditions and have demonstrated that adverse effects are as common as in cancer populations. To our knowledge, no studies comparing oxycodone with other opioids for moderate to severe pain have been conducted in patients with noncancer pain, but there is no clinical or pharmacologic

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reason to believe that one opioid would be more effective than another in one setting (eg, cancer patients) compared with another (eg, patients with chronic noncancer pain). Morphine, in both normaland modified-release formulations, has been the first-line opioid in England for the management of moderate to severe cancer pain. In this review, we did not find any important differences between oxycodone and morphine. Oxycodone is almost 4 times more expensive than morphine in England, and there is less general experience of its use. Thus, there is no reason to challenge the recommendation to use morphine as a first-line agent for cancer pain. There is a need, however, for larger trials of longer duration designed to obtain comparative efficacy and adverse event data for opioids for moderate to severe pain in cancer and noncancer populations.

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