***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: Codeine is widely used in combination with acetaminophen and aspirin for the management of mild to moderate pain . However , there are few controlled clinical trials of single-entity codeine in chronic cancer pain .  The purpose of this study was to evaluate the clinical efficacy and safety of controlled-release codeine given every 12 hr in patients with cancer pain . Thirty-five patients with chronic cancer pain were r and omized in a double-blind crossover study to controlled-release ( CR ) codeine or placebo , for 7 days each . Pain intensity was assessed at 0800 hr and 2000 hr using a visual analogue scale ( VAS ) and a five-point categorical scale , and the use of " rescue " acetaminophen-plus-codeine ( 300 mg/30 mg every 4 hr as needed ) was recorded . Thirty patients completed the study ( 17 male , 13 female ; mean age , 64.4 + /- 9.8 years ) with a mean daily CR codeine dose of 277 + /- 77 mg ( range , 200 - 400 mg ) . CR codeine treatment result ed in significantly lower overall VAS pain intensity scores ( 22 + /- 18 mm versus 36 + /- 20 mm , P = 0.0001 ) , categorical pain intensity scores ( 1.2 + /- 0.8 versus 1.8 + /- 0.8 , P = 0.0001 ) , and pain scores when assessed by day of treatment and by time of day . Daily " rescue " analgesic consumption was significantly lower on CR codeine , compared to placebo treatment ( 2.2 + /- 2.3 versus 4.6 + /- 2.8 tablets per day , P = 0.0001 ) . Both patients and investigators preferred CR codeine to placebo ( 80 % versus 3 % , P = 0.0014 and 73 % versus 7 % , P = 0.0160 , respectively ) . These data indicate that CR codeine , given every 12 hr results in significant reductions in pain intensity and the use of " rescue " acetaminophen-plus-codeine  in patients with cancer pain . CR codeine provides the benefits of a flexible single entity codeine formulation and the convenience of 12-hr duration of action , which allows patients uninterrupted sleep and improved compliance To compare the effectiveness and safety of controlled-release ( CR ) oxycodone tablets with immediate-release ( IR ) oxycodone in patients with chronic cancer pain , a multicenter , r and omized , double-blind , parallel-group study was performed in 111 patients with cancer pain . Patients were treated with 6 to 12 tablets or capsules of fixed-combination opioid/nonopioid analgesics per day at study entry . Patients received 30 mg of CR oxycodone tablets every 12 hr or 15 mg of IR oxycodone four times daily for 5 days . No titration or supplemental analgesic medications were permitted . The mean ( + /- SE ) baseline pain intensity ( 0 = none , 1 = slight , 2 = moderate , 3 = severe ) was 1.5 + /- 0.1 for the CR oxycodone-treated group and 1.3 + /- 0.1 for the group given IR oxycodone ( P > 0.05 ) . The 5-day mean pain intensity was 1.4 + /- 0.1 and 1.1 + /- 0.1 for the CR and IR groups , respectively ( P > 0.05 ) . Discontinuation rates were equivalent ( 33 % ) . There was no significant difference between treatment groups in the incidence of adverse events . This study demonstrates that cancer pain patients given 6 to 12 tablets or capsules of fixed-dose combination analgesics can be equally well treated with CR oxycodone administered every 12 hr or IR oxycodone four times daily at the same total daily dose . CR oxycodone offers the benefits of twice daily dosing Summary Sustained-release morphine ( MST ) given by the rectal route was compared with oral MST in an open r and omised cross-over trial in ten patients with cancer who received stable doses of MST .  No significant difference was found in the areas under the curve of the concentration-time profiles ( AUC ) following oral or rectal administration for parent morphine . The AUCs determine for morphine-6-glucuronide ( M6 G ) and morphine-3-glucuronide ( M3 G ) after oral administration were approximately twice those obtained following rectal administration . The maximal concentration achieved was lower and the time to maximal concentration was longer following rectal administration for morphine , M6 G and M3 G . The relative mean arrival times following rectal administration were significantly longer for morphine and M3 G but not for M6 G . These findings suggest slower absorption but less first-pass metabolism of MST after rectal administration . No significant difference was noted between the oral and the rectal route in measurements on visual-analogue scales for pain or side effects . We recommend the rectal route as being suitable for MST administration when the oral route is no longer available . In changing from oral to rectal administration , the same dose and dose interval may be used , but dose adjustment may be needed & NA ; A controlled trial of diamorphine ( diacetylmorphine , heroin ) and morphine is reported in which the two drugs were administered regularly by mouth in individually determined effective analgesic doses . Elixirs contained cocaine hydrochloride 10 mg/dose ; other drugs were prescribed when indicated clinical ly . 699 patients entered the trial and , of these , 146 crossed from diamorphine to morphine , or vice versa , after about two weeks using an oral potency ratio of 1.5/1 determined in a pilot trial . Additional medication and survival were closely similar in both treatment groups . In the female crossover patients , no difference was noted in relation either to pain or the other symptoms evaluated . On the other h and , male crossover patients experienced more pain , and were more depressed , while receiving diamorphine . In these , the potency ratio of diamorphine  to morphine appeared to be less than 1.5/1 . If this is allowed for , then the difference in mood is probably not significant . Compared with male patients , fewer females required a dose of 10 mg or more , but more were prescribed an anxiolytic . The ability to do without a 2 a.m. dose appeared to be related more to the size of the dose than to gender or treatment . It is concluded that , provided allowance is made for the difference in potency , morphine is a satisfactory substitute for orally administered diamorphine . However , when injections are necessary , the greater solubility of its hydrochloride gives diamorphine an important practical advantage over morphine , especially when large doses are required Immediate‐release oral morphine , given every four hours in individually titrated doses , is effective in the control of  severe cancer pain . To evaluate the analgesic efficacy of a controlled‐release morphine sulfate preparation , MS Contin tablets ( MSC , Purdue Frederick , Toronto , Ontario , Canada ) , after a single dose and under steady‐state conditions , the authors compared MSC administered every 12 hours with morphine oral solution ( MOS ) administered every 4 hours in 17 adult cancer patients with chronic severe pain . In the single‐dose evaluation , in which the patients were r and omly assigned to receive MSC or MOS , there were no significant differences in analgesic efficacy or requirement for supplemental morphine between the two treatments . With both preparations , pain severity ratings increased toward the end of the 12‐hour , single‐dose observation period and were higher than the pain scores reported after dose titration . In the steady‐state evaluation , which was a r and omized crossover comparison , both preparations provided effective pain control with minimal side effects . There was no significant difference between MSC and MOS  in overall pain scores or La pain scores analyzed by time of day and day of therapy . In conclusion , that an individualized twice‐daily regimen of MSC is as effective as 4‐hourly MOS for the control of chronic severe cancer pain . The twice‐daily regimen has several advantages : it allows an uninterrupted night ' sleep , it is substantially more convenient , and it can be expected to reduce both medication errors and noncompliance & 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 Abstract  Variability  in patients ' response to interventions in pain and other clinical setting s is large . Many explanations such as trial methods , environment or culture have been proposed , but this paper sets out to show that the main cause of the variability may be r and om chance , and that if trials are small their estimate of magnitude of effect may be incorrect , simply because of the r and om play of chance . This is highly relevant to the questions of ‘ How large do trials have to be for statistical accuracy ? ’ and ‘ How large do trials have to be for their results to be clinical ly valid ? ’ The true underlying control event rate ( CER ) and experimental event rate ( EER ) were determined from single‐dose acute pain analgesic trials in over 5000 patients . Trial group size required to obtain statistically significant and clinical ly relevant ( 0.95 probability of number‐needed‐to‐treat within ±0.5 of its true value ) results were computed using these values . Ten thous and trials using these CER and EER values were simulated using varying group sizes to investigate the variation due to r and om chance alone . Most common analgesics have EERs in the range 0.4–0.6 and CER of about 0.19 . With such efficacy , to have a 90 % chance of obtaining a statistically significant result in the correct direction requires group sizes in the range 30–60 . For clinical relevance nearly 500 patients are required in each group . Only with an extremely effective drug ( EER>0.8 ) will we be reasonably sure of obtaining a clinical ly relevant NNT with commonly used group sizes of around 40 patients per treatment arm . The simulated trials showed substantial variation in CER and EER , with the probability of obtaining the correct values improving as group size increased . We contend that much of the variability in control and experimental event rates is due to r and om chance alone . Single small trials are unlikely to be correct . If we want to be sure of getting correct ( clinical ly relevant ) results in clinical trials we must study more patients . Credible estimates of clinical efficacy are only likely to come from large trials or from pooling multiple trials of conventional ( small ) size Although the oral route is the preferred method of opioid therapy in patients with cancer pain , many patients will require an alternate route of analgesic administration at some point during the trajectory of their illness . This study compared the efficacy and safety of a novel , controlled-release suppository of morphine ( MSC-R ) and controlled-release morphine tablets ( MSC-T ) in patients with cancer pain . In a double-blind crossover study , 27 patients with cancer pain were r and omized to receive MSC-R or MSC-T every 12 hours for 7 days each , using a 1:1 analgesic equivalence ratio . Pain intensity was assessed using a visual analog scale ( VAS ) and the Present Pain Intensity Index of the McGill Pain Question naire . Nausea and sedation were also assessed with a VAS . Pharmacodynamic assessment s were made by the patient at 8:00 AM , 12:00 PM , 4:00 PM , and 8:00 PM and rescue morphine use recorded in a daily diary . There were no significant differences between MSC-R and MSC-T in overall scores for pain intensity VAS , ordinal pain intensity , and sedation . There was a small but significant difference in overall nausea VAS score in favor of MSC-R.  Mean daily rescue analgesic use did not differ significantly during between treatment with MSC-R and MSC-T. MSC-R provides pain control comparable 
    Output:
    
We found no direct evidence that opioids affected patient consciousness , appetite or thirst when used to treat cancer pain .
However , somnolence , dry mouth , and anorexia were common adverse events in people with cancer pain treated with morphine , fentanyl , oxycodone , or codeine .