***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: The Medical Research Council has for some years encouraged collaborative clinical trials in leukaemia and other cancers , reporting the results in the medical literature . One unreported result which deserves such publication is the development of the expertise to design and analyse such trials . This report was prepared by a group of British and American statisticians , but it is intended for people without any statistical expertise . Part I , which appears in this issue , discusses the design of such trials ; Part II , which will appear separately in the January 1977 issue of the Journal , gives full instructions for the statistical analysis of such trials by means of life tables and the logrank test , including a worked example , and discusses the interpretation of trial results , including brief reports of 2 particular trials . Both parts of this report are relevant to all clinical trials which study time to death , and wound be equally relevant to clinical trials which study time to other particular classes of untoward event : first stroke , perhaps , or first relapse , metastasis , disease recurrence , thrombosis , transplant rejection , or death from a particular cause . Part I , in this issue , collects together ideas that have mostly already appeared in the medical literature , but Part II , next month , is the first simple account yet published for non-statistical physicians of how to analyse efficiently data from clinical trials of survival duration . Such trials include the majority of all clinical trials of cancer therapy ; in cancer trials , however , it may be preferable to use these statistical methods to study time to local recurrence of tumour , or to study time to detectable metastatic spread , in addition to study ing total survival . Solid tumours can be staged at diagnosis ; if this , or any other available information in some other disease is an important determinant of outcome , it can be used to make the overall logrank test for the whole heterogeneous trial population more sensitive , and more intuitively satisfactory , for it will then only be necessary to compare like with like , and not , by chance , Stage I with Stage III Preliminary studies in man of benorylate , 4-(acetamido)phenyl-2-acetoxy-benzoate , have shown that it has antipyretic actions ( Weill , Gaillon , Rendu , and Lejeune , 1968 ; Alex and er , Flahaut , Raveschot , Drykonigen , 1970 ) and an analgesic action significantly superior to placebo and in some instances superior to aspirin ( Vialatel and Gaillon , 1968 ; Hart and Nicholson , 1971 ) . In rheumatoid arthritis , Bain and Burt ( 1970 ) and Cardoe ( 1970 ) have shown that the drug is well tolerated and effective , although the results suggested that their initial dose of 4 g . was inadequate . The pharmacology of benorylate has been reported by Rosner , Malhie , and Mottot ( 1968 ) and the pharmacodynamics of the drug have been described by Robertson ( 1971 ) . Benorylate is well absorbed when taken orally and unlike aspirin its absorption is not influenced by pH. After absorption the molecule undergoes hydrolysis to provide salicylic acid ( SA ) and n-acetyl paraminophenol ( NAPA ) . When compared with aspirin and paracetamol , the peak plasma concentrations ofSA and NAPA are achieved later and more smoothly after benorylate administration . The plateau levels of SA and NAPA obtained after continuous medication are very similar with the three drugs . Excretion of metabolites occurs through the kidney ( 85 per cent . and faeces ( 15 per cent ) . These findings , and the preliminary clinical results , suggested that benorylate merited further assessment in the treatment of rheumatoid arthritis The effectiveness of dothiepin ( a tricyclic anti-depressant ) at a dose of 75 mg given orally at night was compared with placebo for 4 weeks in alleviating pain in 60 patients with classical or definite active rheumatoid arthritis . Patients were classified as either ‘ depressed ’ or ‘ not depressed ’ . The week before , during and 2 weeks after the study , 600 mg ibuprofen was given orally three times daily to all patients . Compared with placebo , dothiepin produced a significant reduction in daytime pain by the end of the treatment period . The Hamilton rating scale in ‘ depressed ’ patients was significantly improved in patients given dothiepin . The Cassano – Castrogiovanni self-evaluation rating scale in both ‘ depressed ’ and ‘ not depressed ’ patients showed a tendency ( not significant ) to be improved following dothiepin treatment compared with placebo . These results suggest that patients with rheumatoid arthritis may experience an increase in pain symptoms due to an alteration of mood . Therapy with tricyclic anti-depressants , such as dothiepin , therefore , may determine an improvement of pain indexes besides having an anti-depressant effect The authors describe a simple non-crossover-blind test for the evaluation of subjective indices . A table for recording pains during the 14 days ' study is described . The patient 's satisfaction with the treatment and the number of days until withdrawal from the trial are recorded . The statistical procedure takes into consideration differences between the treatment groups and makes possible a valuable comparison with drugs tested in other clinical trials . The three dose schedules of antirheumatic treatment were tested on 122 patients and the results compared with those of 342 patients treated with the 6 other antirheumatic drugs ( enteric-coated aspirin , paracetamol , indomethacin , flurbiprofen , mefenamic acid , and prednisolone ) and those of 41 patients who received placebos .  The results show that Safapryn ( 3,6 g aspirin + 3.0 g paracetamol daily ) compared with 3.9 g enteric coated aspirin does not offer any advantage in its analgesic effect , although it gives rise to fewer side effects .  Phenylbutazone ( 3000 mg ) was almost as effective as 15 mg prednisolone daily . Between the effects of this dosage of phenylbutazone and other non-steroidal antirheumatic drugs , however , no significant difference could be detected . 50 mg phenylbutazone daily and placebo treatment could not be distinguished . The authors thank the Arthritis and Rheumatism Council for Research in Great Britain for its financial support . One of the authors ( PL ) was a Merck , Sharp , and Dohme Research Fellow and another one ( PMB ) received a Robins research scholarship Previous studies of combinations of nonsteroidal drugs used in the treatment of rheumatoid arthritis ( RA ) have yielded conflicting results . We used st and ard methods to measure disease activity and high pressure liquid chromatography to measure plasma drug concentrations . We used doses of choline magnesium trisalicylate , adjusted to achieve therapeutic serum salicylate concentrations , and naproxen in a r and omized , double-blind , placebo-controlled cross-over study of full dose trisalicylate ( CMT ) , full dose naproxen ( N ) , full dose of both ( CMT-N ) , and half dose of both ( cmt-n ) to examine their relative efficacy and toxicity in treating RA .  CMT-N was statistically superior to all other treatments in only 1 of 12 efficacy variables , but was equal to N and better than CMT or cmt-n for 7 variables . There were minimal differences among treatments for the other 4 efficacy variables . The mean percentage difference for the efficacy variables between CMT-N and N was 3 % , between CMT-N and CMT was 10.6 % , and between CMT-N and cmt-n was 10.5 % . Thirteen percent of patients manifested toxic reactions during the initial open dose-adjustment salicylate run-in phase . During the double-blind phases of the study , CMT-N was more toxic than N , CMT , or cmt-n ( 7.5 % versus 3.4 % , 1.8 % , and 3.7 % , respectively ) . Tinnitus was more common when full-dose CMT was used ; N ( N or CMT-N ) was associated with increased skin toxicity . Gastrointestinal complaints were equally common with all regimens . CMT-N , although sometimes statistically superior to CMT , N , or cmt-n , showed no clinical ly important additive or synergistic effect versus N or CMT alone Twelve rheumatic patients were given 2.0 and 4.5 g acetylsalicylic acid daily in two 3-week periods . On days 13 and 20 of each period the patients took a suppository containing either placebo or 50 mg of indomethacin . The study was performed double-blind . Indomethacin had a significant additive effect during ASA therapy with 2 g daily as estimated by articular index and subjective ratings of pain and morning stiffness . On the 4.5 g ASA dose there was a significant improvement only for articular index . The patients experienced less pain during maintenance therapy with 4.5 g of ASA compared with 2.0 g daily . Both ASA doses induced complete inhibition of prostagl and in PGF2 alpha release from platelets . Thus the suppression of PGF2 alpha release does not reflect the therapeutic response of these drugs . Side effects observed comprised tinnitus , dizziness and gastritis . In 2 of the patients the aminotransferase levels increased , indicating hepatotoxicity . The protein binding of salicylate decreased with increasing salicylate concentration . As the dose was increased from 2.0 to 4.5 g/day the unbound concentration increased 5 to 24 times . This reflects the combined effect of capacity-limited metabolism and capacity-limited protein binding of salicylate Actions on performance of  dextropropoxyphene ( DXP ) alone and in combination with amitriptyline ( AMI ) , indomethacin ( IN ) , and placebo were compared in 15 patients with rheumatoid arthritis . The patients were on their prescribed maintenance regimen excluding analgesics . In four r and omized test sessions at two-week intervals , they received double blind and crossover single oral doses of DXP 130 mg , IN 50 mg , DXP 65 mg + AMI 25 mg or placebo , each after two days ' pretreatment with the same drug . Objective and subjective effects were measured at baseline and 2 and 4 hours after drug administration . DXP impaired critical flicker discrimination , symbol copying and body balance without modifying tracking , choice reactions or attention . It rendered the subjects elated , muzzy , mentally slow and calm . Actions of AMI + DXP were about the same . IN impaired body balance and critical flicker recognition . Plasma concentrations of DXP were moderate to high whilst those of IN and AMI were fairly low . We conclude that therapeutic doses of DXP and IN are relatively safe in regard to driving skills . Small doses of AMI may not enhance the mild psychomotor effects of DXP . Earlier single dose studies carried out with healthy volunteers might have overestimated the decremental effects of analgesics on psychomotor performance In a double-blind between-patient study of aspirin and benorylate carried out in 72 out patients with rheumatoid arthritis , benorylate 4 g twice daily was shown to be an effective analgesic and anti-inflammatory drug , its effects being indistinguishable from those of aspirin 1·2 g four times daily . Compared with the pretreatment values both drugs produced a statistically significant improvement ( P < 0·01 ) in functional grade , overall pain , articular index , and grip strength at the end of the first and second weeks . The overall incidence of side effects was less with benorylate , though this difference was not significant at the 5 % level & NA ; R and omized , double‐blind , placebo‐controlled trials on neuropathic pain treatment are accumulating , so an up date d review of the available evidence is needed . Studies were identified using MEDLINE and EMBASE search es . Numbers needed to treat ( NNT ) and numbers needed to harm ( NNH ) values were used to compare the efficacy and safety of different treatments for a number of neuropathic pain conditions . One hundred and seventy‐four studies were included , representing a 66 % increase in published r and omized , placebo‐controlled trials in the last 5 years . Painful poly‐neuropathy ( most often due to diabetes ) was examined in 69 studies , postherpetic neuralgia in 23 , while peripheral nerve injury , central pain , HIV neuropathy , and trigeminal neuralgia were less often studied . Tricyclic antidepressants , serotonin noradrenaline reuptake inhibitors , the anticonvulsants gabapentin and pregabalin , and opioids are the drug classes for which there is the best evidence for a clinical relevant effect . Despite a 66 % increase in published trials only a limited improvement of neuropathic pain treatment has been obtained . A large proportion of neuropathic pain patients are left with insufficient pain relief . This fact calls for other treatment options to target chronic neuropathic pain . Large‐scale drug trials that aim to identify possible subgroups of patients who are likely to respond to specific drugs are needed to test the hypothesis that a mechanism‐based classification may help improve treatment of the individual patients The therapeutic and adverse effects of 2 weeks of treatment with high-dose indomethacin ( 150 mg/day ) were compared with those of low-dose indomethacin ( 50 mg/day ) combined with paracetamol ( 4 g/day ) in a double-blind , double-dummy , cross-over study in 17 patients with active rheumatoid arthritis .  Grip strength , Ritchie 's index , joint circumference , joint pain , and patient 's and physician 's global assessment s were estimated , and conventional laboratory parameters were followed . In addition , the time-concentration profiles of indomethacin and paracetamol were assessed during steady state 
    Output:
    
In general , there were no differences in safety and withdrawals due to inadequate analgesia between combination and monotherapy .
Based on 23 trials , all at high risk of bias , there is insufficient evidence to establish the value of combination therapy over monotherapy for pain management in IA .