***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: & NA ; Oral transmucosal fentanyl citrate ( OTFC ® ; Actiq ® ) is a drug delivery formulation used for management of breakthrough cancer pain . Previous studies with open‐label comparisons indicated OTFC was more effective than patients ’ usual opioid for breakthrough pain . The objective of this study was to compare OTFC and morphine sulfate immediate release ( MSIR ® ) for management of breakthrough pain in patients receiving a fixed scheduled opioid regimen . This double‐blind , double‐dummy , r and omized , multiple crossover study was conducted at 19 US university‐ and community‐based hospitals and clinics and comprised 134 adult ambulatory cancer patients . Patients were receiving a fixed scheduled opioid regimen equivalent to 60–1000 mg/day oral morphine or 50–300 & mgr;g/h transdermal fentanyl  , were using a ‘ successful ’ MSIR dose ( 15–60 mg ) as defined by entry criteria , and were experiencing 1–4 episodes of breakthrough pain per day . In open‐label fashion , OTFC was titrated such that a single unit ( 200–1600 & mgr;g ) provided adequate pain relief with acceptable side effects . Successfully titrated patients entered the double‐blind phase of the study and received ten prenumbered sets of r and omized capsules and oral transmucosal units . Five sets were the successful OTFC dose paired with placebo capsules , and five sets were placebo OTFC paired with capsules containing the successful MSIR dose . Patients took one set of study medication for each episode of target breakthrough pain . Pain intensity ( PI ) , pain relief ( PR ) and global performance of medication ( GP ) scores were recorded . Pain intensity differences ( PID ) were calculated and 15‐min PID was the primary efficacy variable . Adverse events were recorded . Sixty‐nine percent of patients ( 93/134 ) found a successful dose of OTFC . OTFC yielded outcomes ( PI , PID , and PR ) at all time points that were significantly better than MSIR . GP also favored OTFC and more patients opted to continue with OTFC than MSIR following the study . Somnolence , nausea , constipation , and dizziness were the most common drug‐associated side effects . In conclusion , OTFC was more effective than MSIR in treating breakthrough cancer pain A new 72-hour transdermal fentanyl matrix patch has been design ed , which has a 35%-50 % reduction of the absolute fentanyl content compared with other currently available transdermal fentanyl patches that are using the matrix technology . The new patch has previously been shown to be pharmacokinetically bioequivalent to the marketed fentanyl patch . To determine noninferiority in efficacy in cancer patients and to compare safety , a clinical trial comparing the new fentanyl patch with st and ard oral or transdermal opioid treatment was planned . The design was an open , parallel group , multicenter trial , in which 220 patients were r and omized to receive either the fentanyl patch or st and ard opioid treatment for 30 days . The primary efficacy variable , pain intensity ( PI ) on a 0 - 10-point numerical rating scale , was recorded once daily . The primary endpoint was the relative area under the curve of PI expressed as a percentage of the maximum possible PI area under the curve . Any adverse events were recorded ; four tolerability endpoints , constipation , nausea , daytime drowsiness , and sleeping disturbances , were assessed daily . Noninferiority was shown ; the upper 95 % confidence interval limits of the mean difference in relative PI area under the curve between the fentanyl patch and st and ard opioid treatment were less than 10 % for both the intention-to-treat and per- protocol population s. Scores for the tolerability endpoints were similar in the treatment groups . The new fentanyl matrix patch with a lower drug load was found noninferior and as safe as established st and ard oral and transdermal opioid treatment The antinociceptive effect of morphine and oxycodone is mediated preferentially at μ and κ receptors , respectively . The aim of this study was to evaluate the analgesic profile of the combination of morphine and oxycodone in cancer pain , compared to the st and ard administration of morphine alone . Controlled-release formulations of oxycodone ( CRO ) and morphine ( CRM ) were compared in 26 patients . The study started with an open-label , r and omised titration phase to achieve stable pain control for 7 days , followed by a double-blind , r and omised crossover phase in two periods , 14 days each . At any point , patients were allowed to use oral immediate-release morphine ( IRM ) as needed , in order to keep visual analogue scale ⩽4 . Pain , satisfaction , adverse effects and number of daily rescue morphine tablets were assessed . A total of 22 patients were evaluated .  The weekly upload consumption ratio in morphine/oxycodone was 1 : 1.8 ( 1.80 , 1.83 , 1.76 , 1.84 ) . The weekly IRM consumption was higher in patients having CRM compared to patients having CRO ( ratio morphine/oxycodone : 1.6 , 1.6 , 1.6 , 1.7 ) ( P<0.05 ) . Patients receiving oxycodone complained of less nausea and vomiting . The rescue morphine analgesic consumption was 38 % higher in patients receiving only morphine , compared to patients receiving both morphine and oxycodone . The results suggest that the combination of morphine/oxycodone ( opioids with differential preferential sites of action ) can be a useful alternative to morphine alone , result ing in a better analgesia profile and less emesis Oxycodone is an opioid analgesic that closely resembles morphine . Oxymorphone , the active metabolite of oxycodone , is formed in a reaction catalyzed by CYP2D6 , which is under polymorphic genetic control . The role of oxymorphone in the analgesic effect of oxycodone is not yet clear . In this study , controlled-release ( CR ) oxycodone and morphine were examined in cancer pain . CR oxycodone and morphine were administered to 45 adult patients with stable pain for 3 - 6 days after open-label titration in a r and omized , double-blind , cross-over trial . Twenty patients were evaluable . Both opioids provided adequate analgesia . The variation in plasma morphine concentrations was higher than that of oxycodone , consistent with the lower bioavailability of morphine . Liver dysfunction affected selectively either oxycodone or morphine metabolism . Three patients with markedly aberrant plasma opioid concentrations are presented . Significant individual variation in morphine and oxycodone metabolism may account for abnormal responses during treatment of chronic cancer pain Cancer patients requiring strong opioid analgesia ( n = 202 ; mean age , 61.5 years ; range , 18 - 89 years ; 55 % men ) were recruited from 38 United Kingdom palliative care centers into a r and omized , open , two-period , crossover study comparing transdermal fentanyl with sustained-release oral morphine . Patients received one treatment for 15 days followed immediately by the other for 15 days . Daily diaries were completed . Both treatments appeared equally effective in terms of pain control , as assessed by the Memorial Pain Assessment Card and European Organization for Research and Treatment of Cancer ( EORTC ) pain scores .  Fentanyl was associated with significantly less constipation ( p < 0.001 ) and less daytime drowsiness ( p = 0.015 ) but greater sleep disturbance ( p = 0.004 ) and shorter sleep duration ( p = 0.008 ) than morphine . The World Health Organization ( WHO ) performance status and EORTC global quality of life scores showed no significant difference between treatment groups . Of those patients who were able to express a preference ( n = 136 ) , significantly more preferred the fentanyl patches ( p = 0.037 ) . We conclude that , in this study , transdermal fentanyl provided pain relief that was acceptable to cancer patients and was associated with less constipation and sedation than morphine . These reduced side effects may contribute to patients preference for the patches The European Association for Palliative Care guidelines for treatment of cancer pain recommend a double dose ( DD ) of immediate-release morphine at bedtime instead of single doses ( SD ) repeated every four hours throughout the night . A previous open controlled study reported more side effects after DD than after SD . The present study was a r and omized , double-blind , crossover study comparison of DD and SD of immediate-release morphine during the night , followed by an open pharmacokinetic study . The primary outcome was average pain intensity during the night , as measured on an 11-point numerical rating scale . Secondary outcomes were morning pain , number of rescue medications , adverse effects ( nausea , xerostomia , tiredness , sleep quality , and number of awaking episodes ) and patient preference . Morphine and metabolites were quantified by a vali date d liquid chromatography-t and em mass spectrometry method . Nineteen patients completed the clinical study ; 13 participated in the pharmacokinetic follow up .  Average pain during the night for DD vs. SD was close to statistical significance ( mean 0.8 and 1.4 , respectively , P=0.058 ; mean [ 95 % confidence interval ] for the difference was 0.50 [ 0.02 , 1.0 ] ) . A similar trend was observed for strongest night pain ( P=0.069 ) and sleep quality ( P=0.077 ) . Only two patients required rescue morphine .  Four patients had no treatment preference ; nine and six favored DD and SD , respectively . DD patients displayed higher area under the curve for morphine and morphine-6-glucuronide during the first part of the night . Although DD tended to perform slightly better than SD , a difference in average pain during the night of 0.50 has little clinical significance , and the two procedures are , therefore , clinical ly equivalent . It is speculated whether the initial higher exposure to morphine-6-glucuronide may have clinical significance Background Long-acting opioid formulations are advocated for maintaining pain control in chronic cancer pain .  OROS ® hydromorphone is a sustained-release formulation of hydromorphone that requires dosing once daily to maintain therapeutic concentrations . The objective of this study was to demonstrate the clinical equivalence of immediate-release and sustained-release formulations of hydromorphone and morphine for chronic cancer pain . Methods 200 patients with cancer pain ( requiring ≤ 540 mg/d of oral morphine ) participated in this double-blind , parallel-group trial . Patients were r and omized to receive hydromorphone or morphine ( immediate-release for 2–9 days , sustained-release for 10–15 days ) . Efficacy was assessed with the Brief Pain Inventory ( BPI ) , investigator and patient global evaluations , Eastern Cooperative Oncology Group performance status , and the Mini-Mental State Examination . The primary endpoint was the ' worst pain in the past 24 hours ' item of the BPI , in both the immediate-release and sustained-release study phases , with treatments deemed equivalent if the 95 % confidence intervals ( CI ) of the between-group differences at endpoint were between -1.5 and 1.5 . No equivalence limits were defined for secondary endpoints . Results Least-squares mean differences ( 95 % CI ) between groups were 0.2 ( -0.4 , 0.9 ) in the immediate-release phase and -0.8 ( -1.6 , -0.01 ) in the sustained-release phase ( intent-to-treat population ) , indicating that the immediate-release formulations met the pre-specified equivalence criteria , but that the lower limit of the 95 % CI ( -1.6 ) was outside the boundary ( -1.5 ) for the sustained-release formulations . BPI ' pain now PM ' was significantly lower with OROS ® hydromorphone compared with controlled-release morphine ( least-squares mean difference [ 95 % CI ] , -0.77 [ -1.49 , -0.05 ] ; p = 0.0372 ) . Scores for other secondary efficacy variables were similar between the two sustained-release treatments . At endpoint , > 70 % of investigators and patients rated both treatments as good to excellent . The safety profiles of hydromorphone and morphine were similar and typical of opioid analgesics . Conclusion Equivalence was demonstrated for immediate-release formulations of hydromorphone and morphine , but not for the sustained-release formulations of OROS ® hydromorphone and controlled-release morphine . The direction of the mean difference between the treatments ( -0.8 ) and the out-of-range lower limit of the 95 % CI ( -1.6 ) were in favor of OROS ® hydromorphone . Trial registration Clinical Trials.gov : BACKGROUND Opioid and spinal monoaminergic agonists have distinct analgesic properties , which may potentiate each other . Tramadol has both opioid and monoaminergic agonist actions . This initial study compared the analgesic and toxic effects of tramadol and morphine in patients with strong cancer pain . PATIENTS AND METHODS Pain control and side-effects with tramadol and morphine were compared in 20 cancer patients hospitalised for the treatment of strong pain . Doses of oral solutions of tramadol or morphine were individually titrated in the double-blind , r and omized , cross-over study . Cross-over was after day 4 , the day of statistical evaluation . RESULTS The mean pain intensity ( + /- SD ) on a verbal rating scale ( 0 = none , 4 = unbearable ) was similar with morphine ( 1.6 + /- 1.2 , n = 17 ) and with tramadol ( 1.5 + /- 1.3 , n = 16 ) 
    Output:
    
These studies do not add significant information to the previous Cochrane review confirming the limitation of efficacy and tolerability data on opioid-naïve and non-selected population s of cancer patients treated with morphine and suggesting that oral morphine , oxycodone and hydromorphone have similar efficacy and toxicity in this patient population