***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: Objectives This study aims to evaluate the efficacy of methadone as substitute for morphine and to investigate if the addition of acetaminophen could reduce the time to attain an equianalgesic dose of methadone and /or to improve the level of pain control in oncologic patients . Patients and methods Fifty patients on stable doses of morphine for 1 week were switched to methadone using a “ stop – start ” strategy and r and omized in a double-blind fashion to receive either acetaminophen ( 750 mg PO every 6 hours ) or placebo for a 7-day period . We collected data regarding level of pain , side effects , and quality of life . Results Substitution of morphine for methadone result ed in a significant reduction in constipation ( p < 0.001 ) and xerostomia ( p = 0.03 ) . There was also an improvement in the numeric pain scale ( p = 0.03 ) as well as a significant improvement in the functional level and symptomatology according to the QLQ-C30 question naire . Addition of acetaminophen did not improve pain control or reduce the time of stabilization of analgesia once methadone was introduced . At the end of the study , most patients ( 70.8 % , p = 0.001 ) preferred methadone to morphine . Conclusions Early switching from morphine to methadone was a safe and efficient strategy for the reduction of side effects and improvement of analgesia , allowing for a comfortable dosing regimen . In this scenario , the association with acetaminophen did not improve pain control or reduce the time to achieve an equianalgesic dose of methadone The role of non-steroidal anti-inflammatory drugs ( NSAIDs ) in cancer pain has been well established in the treatment of mild pain and in association with opioids in the treatment of moderate to severe pain . The aim of this study was to verify the effects of NSAIDs on morphine escalation in advanced cancer patients with pain followed-up at home and to assess the pharmacoeconomic implication s. A prospect i ve r and omised controlled study was carried out in 156 consecutive advanced cancer patients with pain followed-up at home in the period December 1999-December 2000 . In this group of patients , 47 were selected with pain progression after 1 week of opioid stabilisation . Patients were r and omly assigned to one of two groups : group ' O ' patients were treated with continuing opioid escalation according to their clinical needs ; group ' OK ' received ketorolac 60 mg/daily orally ( p.o . ) in three doses and then continued opioid escalation according to their clinical situation . Performance status , doses of morphine before and after starting treatment , mean weekly pain intensity ( assessed by means of a numerical scale from 0 to 10 ) , mean weekly symptoms intensity , adverse effects and pain mechanisms were recorded . Moreover , drug costs per day in both groups were calculated . Patients who received ketorolac in addition to morphine showed a better analgesia after a week in comparison to the group treated with morphine only ( P=0.005 ) . Thereafter ,  morphine escalation was slower and the maximum  morphine dose was lower in the group treated with ketorolac . The incidence and the severity of gastric discomfort was more evident in patients treated with ketorolac , while constipation was significantly increased in patients who received morphine only . Drug costs per day were similar in both groups ; statistical differences were observed in patients who started on lower morphine doses ( < 100 mg/daily ) in the two groups ( 4.3 in the ketorolac-morphine group versus 3.4 in the morphine group ; P=0.012 ) . The use of NSAIDs reduces the need for an opioid dose escalation or allows the use of lower doses . Their use is associated with a more intense gastric discomfort , but results in less opioid-related constipation . The eventual additive cost for NSAIDs therapy is negligible , especially in patients taking high doses of morphine Introduction Adjunct nonopioid analgesics may improve pain control in patients with cancer needing morphine or its derivates .  Dypirone is a cheap nonopioid analgesic widely used in many countries . Objective The objective of the study was to evaluate , whenever morphine was started , if associating dipyrone with it would improve pain control and if this effect was time dependent . Material s and methods This is a double-blind placebo-controlled r and omized crossover study . Thirty-four ambulatory cancer patients experiencing cancer-related pain for which oral morphine was to be started at the dose of 10 mg orally ( PO ) every 4 h were r and omized to take either dipyrone 500 mg PO every 6 h or placebo . After 48 h , patients would be switched from dipyrone to placebo and vice versa . Pain was the primary outcome and was measured using a visual analogue scale before starting medications , at 48 and 96 h. Results We r and omized 16 patients to start with placebo ( group 1 ) and 18 with dipyrone ( group 2 ) .  Pain scores for groups 1 and 2 were at baseline : 7.31 ± 0.29 vs 6.88 ± 0.28 ( p = 0.3 ) , at 48 h : 7.06 ± 0.32 vs 5.5 ± 0.31 ( p = 0.001 ) , and at 96 h : 3.18 ± 0.39 vs 1.94 ± 0.37 ( p = 0.03 ) . Both groups had significant improvements in pain scores after introducing dipyrone ( p < 0.001 , for both ) . Main toxicities were nausea , vomiting , epigastric pain , and myalgias . Twenty-eight patients chose dipyrone , four placebo , and two were indifferent . Conclusions We conclude that dipyrone adds significantly to the analgesic effect of morphine and , when given at the time of starting morphine , results in better pain scores even after dipyrone is discontinued & NA ;  Pain intensity is frequently measured on an 11‐point pain intensity numerical rating scale ( PI‐NRS ) , where 0=no pain and 10=worst possible pain . However , it is difficult to interpret the clinical importance of changes from baseline on this scale ( such as a 1‐ or 2‐point change ) . To date , there are no data driven estimates for clinical ly important differences in pain intensity scales used for chronic pain studies . We have estimated a clinical ly important difference on this scale by relating it to global assessment s of change in multiple studies of chronic pain . Data on 2724 subjects from 10 recently completed placebo‐controlled clinical trials of pregabalin in diabetic neuropathy , postherpetic neuralgia , chronic low back pain , fibromyalgia , and osteoarthritis were used . The studies had similar design s and measurement instruments , including the PI‐NRS , collected in a daily diary , and the st and ard seven‐point patient global impression of change ( PGIC ) , collected at the endpoint . The changes in the PI‐NRS from baseline to the endpoint were compared to the PGIC for each subject . Categories of ‘ much improved ’ and ‘ very much improved ’ were used as determinants of a clinical ly important difference and the relationship to the PI‐NRS was explored using graphs , box plots , and sensitivity/specificity analyses . A consistent relationship between the change in PI‐NRS and the PGIC was demonstrated regardless of study , disease type , age , sex , study result , or treatment group . On average , a reduction of approximately two points or a reduction of approximately 30 % in the PI‐NRS represented a clinical ly important difference . The relationship between percent change and the PGIC was also consistent regardless of baseline pain , while higher baseline scores required larger raw changes to represent a clinical ly important difference . The application of these results to future studies may provide a st and ard definition of clinical ly important improvement in clinical trials of chronic pain therapies . Use of a st and ard outcome across chronic pain studies would greatly enhance the comparability , validity , and clinical applicability of these studies Cobrotoxin produces intense analgesia but it has an onset of response of 1 - 3 h which hampers its clinical use in cancer pain . Recently , a compound analgesic formulation combining cobrotoxin , tramadol hydrochloride and ibuprofen ( Compound Keluoqu , CKLQ ) has become available in China . The aim of this study was to evaluate the clinical efficacy of CKLQ for moderate to severe cancer pain . A consecutive series of patients with chronic moderate to severe cancer pain was enrolled into two multicenter trials . Of the 230 eligible patients , 119 were assigned to a r and omized , double-blind , cross-over study , while 111 entered an open-label study . They were all of Han-China nationality and had a mean age of 52.0 and 55.4 years and a mean body weight of 55.6 and 52.9 kg , respectively . A total of 11 patients discontinued the study , 6 ( 54.5 % ) because of insufficient pain relief and 5 due to the occurrence of adverse events . In the cross-over study , 59 patients were r and omized to receive a CKLQ package with 2 CKLQ tablets ( each containing 0.16 mg cobrotoxin , 25 mg tramadol hydrochloride and 50 mg ibuprofen ) and 2 placebo capsules , a placebo package with 2 placebo tablets and 2 placebo capsules , and an active control package with 2 tramadol hydrochloride capsules ( each containing 50 mg tramadol hydrochloride ) and 2 placebo tablets ( arm A ) , and 60 to receive a tramadol hydrochloride package , a placebo package and a CKLQ package ( arm B ) , sequentially and only once . Patients in the open-label study only received CKLQ and were given the option to continue for up to 7 days as long as they had satisfactory pain relief . Pain response was classified as CR , PR and NC . CR was defined as 100 % pain relief , with a pain score of 0 on a 0 - 10 VAS . PR was defined as decreased to mild pain , with a pain score of no more than 4 on a 0 - 10 VAS . NC was defined as pain that either remained unchanged or that was reduced from severe to moderate at baseline , with a VAS pain score of more than 4 after treatment . One hundred and eight patients completed the cross-over study with all the three drug units . The overall rate of pain relief was 93/111 ( 83.7 % ) for CKLQ , 75/110 ( 68.2 % ) for tramadol hydrochloride ( P=0.011 ) and 39/111 ( 35.1 % ) for placebo ( P<0.001 ) . The mean duration of pain relief with CKLQ was significantly longer than that of the other two agents ( P<0.001 ) . Of the 35 patients who did not respond to tramadol hydrochloride , 27 ( 77.1 % ) responded to CKLQ , while of the 18 who did not respond to CKLQ , 8 ( 55.6 % ) achieved satisfactory pain control with tramadol hydrochloride . In the open-label study , the overall relief rate of a single-dose of CKLQ was 99/111 ( 89.2 % ) . A reduction in the percentage of complete relief , an increase in that of PR and a significant decrease in duration of relief were observed after continuous treatment with at least 10 doses of CKLQ . The frequency of adverse events for CKLQ was similar to that of tramadol hydrochloride . The results of the r and omized , double-blind , cross-over study and the open-label study of CKLQ in cancer patients with chronic moderate to severe cancer pain suggest that the CKLQ may be valuable for the treatment of chronic moderate to severe cancer pain . However , the tolerance of CKLQ remains to be further defined Objetives The purpose of this study was to compare the analgesic efficacy and tolerability of opioids hydrocodone and tramadol in the relief of  cancer pain .  Methods One hundred and eighteen patients with chronic cancer pain participated in a double-blind , r and omized controlled trial . Sixty-two patients received hydrocodone and 56 patients received tramadol . Results Hydrocodone/acetaminophen was effective in relieving pain in 56.5 % of the patients at the starting dose of 25 mg/2500 mg/d . An additional 14.5 % of the patients responded to a double dose , and the remaining 29 % of patients did not experience any pain relief from hydrocodone administration . One dose of tramadol at 200 mg/d produced pain relief in 62 % of the patients and alleviated pain in another 11 % of patients at a dose of 400 mg/d , and remaining 27 % of patients did not experience pain relief from tramadol . No significant statistical difference in the analgesic efficacy of tramadol clorhydrate and hydrocodone/acetaminophen was found . The groups differed significantly in the incidence of side effects like nausea ( P=0.03 ; relative risk ( RR ) , 1.69 ; confidence interval ( IC ) 95 % , 1.03 - 2.77 ) , vomiting ( P=0.02 ; RR , 2.21 ; IC 95 % , 1.14 - 4.32 ) , dizziness ( P=0.03 ; RR , 2.12 ; IC 95 % , 1.17 - 3.86 ) , loss of appetite ( P=0.02 ; RR , 3.27 ; IC 95 % , 1. 
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There is no proof that they should be used to start the treatment and how long they should be administered when opioid treatment is added on top .
While paracetamol seems to be devoid of any benefit , particularly if given at usual clinical doses which should be less than 4 g/day , ketorolac seems to provide an additive analgesic effect even in patients receiving different doses of opioids .
The main indication from the analysis of these data is that NSAIDs could be given in patients receiving opioids , evaluating their benefit and weight on opioid therapy  in individual patients who have a favorable response to justify a prolonged use