***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 open‐label follow‐on trial aim ed to investigate long‐term safety and efficacy of lacosamide in patients with painful diabetic neuropathy Background There are few repeated dose-controlled trials of N-methyl-d-aspartate glutamate receptor antagonists in patients with neuropathic pain . The authors sought to evaluate two low-affinity N-methyl-d-aspartate antagonists using a novel two-stage design . Methods The authors studied patients with painful diabetic neuropathy ( DN ) and postherpetic neuralgia ( PHN ) in two crossover trials : ( 1 ) efficacy trial ( dextromethorphan vs. memantine vs. active placebo [ lorazepam ] ) and ( 2 ) dose – response trial of the preferred active drug in responders from the first study ( 0%vs . 25%vs . 50%vs . 100 % of each patient 's maximally tolerated dose ) . Pain intensity was measured on a 20-point scale . Results Nineteen of 23 DN patients and 17 of 21 PHN patients completed the efficacy trial .  Median doses for DN and PHN were 400 and 400 mg/day dextromethorphan , 55 and 35 mg/day memantine , and 1.8 and 1.2 mg/day lorazepam . In the efficacy trial , among patients with DN , dextromethorphan  reduced pain intensity by a mean of 33 % from baseline , memantine  reduced pain intensity by a mean of 17 % , and lorazepam  reduced pain intensity by a mean of 16 % ; the proportions of subjects achieving greater than moderate pain relief were 68 % with dextromethorphan , 47 % with memantine , and 37 % with lorazepam .  Mean reductions in pain intensity in patients with PHN were 6 % with dextromethorphan , 2 % with memantine , and 0 % with lorazepam . No comparison with placebo reached statistical significance in the efficacy trial . In the 10 DN subjects who responded to dextromethorphan , there was a significant dose – response effect on pain intensity ( P = 0.035 ) , with the highest dose significantly better than that of lorazepam ( P = 0.03 ) . Conclusions Dextromethorphan is effective in a dose-related fashion in selected patients with DN . This was not true of PHN , suggesting a difference in pain mechanisms . Selective approaches to pain-relevant N-methyl-d-aspartate receptors are warranted Background Peripheral diabetic neuropathy affects between 20 % and 45 % of patients with diabetes . Objective To ascertain the effect of lacosamide on pain associated with peripheral diabetic neuropathy . Methods One hundred nineteen patients with a 1 to 5-year history of pain attributed to diabetic neuropathy and a score of ≥4 on the Likert pain scale entered the multicenter , r and omized , double-blind , placebo-controlled trial . Lacosamide ( N=60 ) titrated from 100 to 400 mg/d or maximum tolerated dose and placebo ( N=59 ) were the trial interventions . Primary efficacy criterion was change in pain score on the 11-point Likert pain scale . Secondary assessment s included Short-Form McGill Pain and Short-Form-36 Quality of Life Question naires , sleep/activity interference , pain intensity , Patient and Clinical Global Impression of Change , and Profile of Mood .  Patients receiving at least 1 dose of medication underwent safety evaluation . Results Ninety-four patients ( lacosamide 46 ; placebo 48 ) completed the trial . Lacosamide had significantly ( P=0.039 ) better pain relief  versus placebo ( primary outcome ) . Improvements were also seen in secondary outcome measures . Adverse events occurred in 52 lacosamide and 44 placebo patients . Common adverse events , occurring in ≥5 % of patients , were headache  ( lacosamide 18 % , placebo 22 % ) , dizziness  ( lacosamide 15 % , placebo 8 % ) , and nausea  ( lacosamide 12 % , placebo 7 % ) . Five lacosamide and 3 placebo patients withdrew for adverse events . Discussion Lacosamide seems to attenuate pain in diabetic neuropathy in doses up to 400 mg/d and improves quality of life issues & NA ; The aim of this study was to examine the efficacy and safety of duloxetine , a balanced and potent dual reuptake inhibitor of serotonin and norepinephrine , in the management of  diabetic peripheral neuropathic pain . Serotonin and norepinephrine are thought to inhibit pain via descending pain pathways . In a 12‐week , multicenter , double‐blind study , 457 patients experiencing pain due to polyneuropathy caused by Type 1 or Type 2 diabetes mellitus were r and omly assigned to treatment with duloxetine 20 mg/d ( 20 mg QD ) , 60 mg/d ( 60 mg QD ) , 120 mg/d ( 60 mg BID ) , or placebo . The diagnosis was confirmed by a score of at least 3 on the Michigan Neuropathy Screening Instrument . The primary efficacy measure was the weekly mean score of the 24‐h Average Pain Score , which was rated on an 11‐point ( 0–10 ) Likert scale ( no pain to worst possible pain ) and computed from diary scores between two site visits . Duloxetine 60 and 120 mg/d demonstrated statistically significant greater improvement compared with placebo  on the 24‐h Average Pain Score , beginning 1 week after r and omization and continuing through the 12‐week trial . Duloxetine also separated from placebo on nearly all the secondary measures including health‐related outcome measures . Significantly more patients in all three active‐treatment groups achieved a 50 % reduction in the 24‐h Average Pain Score  compared with placebo . Duloxetine treatment was considered to be safe and well tolerated with less than 20 percent discontinuation due to adverse events . Duloxetine at 60 and 120 mg/d was safe and effective in the management of diabetic peripheral neuropathic pain & 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 UNLABELLED Data on 1,700 patients pooled from 5 r and omized , placebo-controlled duloxetine studies ( 3 in diabetic peripheral neuropathic pain and 2 in fibromyalgia ) were analyzed to determine clinical ly important differences ( CIDs ) in the 0 to 10 Numeric Rating Scale-Pain Intensity ( NRS-PI ) for patient-reported " worst " and " least " pain intensity while validating the previously published level for " average " pain . The correspondence between the baseline-to-endpoint raw and percentage change in the NRS-PI for the worst , least , and average pain were compared to patients ' perceived improvements at endpoint as measured by the 7-point Patient Global Impression of Improvement ( PGI-I ) scales . Stratification by baseline pain separated the raw but not the percent change scores . The PGI-I category of " much better " or above was our a priori definition of a CID . Cutoff points for the NRS-PI change scores were determined using a receiver operator curve analysis . A consistent relationship between the worst and average NRS-PI percent change and the PGI-I was demonstrated regardless of the study , pain type , age , sex , or treatment group with a reduction of approximately 34 % . The least pain item CID was slightly higher at 41 % . Raw change CID cutoff points were approximately -2 , -2.5 and -3 for least , average , and worst pain respectively . PERSPECTIVE We determined an anchor-based value for the change in the worst , least , and average pain intensity items of the Brief Pain Inventory that best represents a clinical ly important difference . Our findings support a st and ard definition of a clinical ly important difference in clinical trials of chronic-pain therapies A controlled clinical trial on the efficacy of a nortriptyline-fluphenazine combination was carried out in patients with painful diabetic polyneuropathy . A visual analog scale was used to evaluate the relief of pain or paresthesia . Significant relief of both pain and paresthesia was obtained with this combination . The differences were statistically significant . Side effects were frequent but not usually severe enough to lead to cessation of these medications Background and objective : Opioid treatment has played a limited role in the management of diabetic neuropathy , in part because of concerns about the responsiveness of neuropathic pain to opioid treatment . This controlled study evaluated the efficacy and safety of controlled-release ( CR ) oxycodone in subjects with moderate to severe pain due to diabetic neuropathy . Methods : This multicenter , r and omized , double-blind , placebo-controlled , parallel-group study included 159 subjects with moderate to severe pain due to diabetic neuropathy . Treatment began with either one 10-mg tablet of CR oxycodone ( n = 82 ) or identical placebo ( n = 77 ) every 12 hours . Doses could be increased every 3 days to a maximum of 6 tablets ( 60 mg CR oxycodone ) every 12 hours . Treatment lasted up to 6 weeks . The primary efficacy variable was overall average daily pain intensity during study days 28 to 42 . Results : At an average ( SD ) dose of 37 ( 21 ) mg per day ( range 10 to 99 mg/d ) , CR oxycodone provided more analgesia  than placebo ( p= 0.002 ) in the intent-to-treat cohort . From days 28 to 42 , overall average daily pain intensity ( least squares mean ±SE ) , rated in subject diaries on a numeric scale of 0 ( no pain ) to 10 ( pain as bad as you can imagine ) , was 4.1 ± 0.3 in subjects given CR oxycodone and 5.3 ± 0.3 in placebo-treated subjects . Overall , 80 ( 96 % ) of 82 subjects given CR oxycodone and 52 ( 68 % ) of 77 subjects who received placebo  reported adverse events . The most common adverse events in the CR oxycodone group were opioid related . Conclusions : In this 6-week trial , CR oxycodone was effective for the treatment of moderate to severe pain due to diabetic neuropathy . Adverse events were typical of opioid-related side effects Objectives The aims of this multicenter , r and omized , placebo-controlled , double-blind trial were to confirm the efficacy of lacosamide at a daily dose of 400 mg/d and to explore the efficacy , safety , and tolerability of lacosamide 200 mg/d and 600 mg/d in the treatment of painful diabetic neuropathy . Methods The trial consisted of a 2-week run-in period , a 6-week titration phase , and a 12-week maintenance phase , during which patients received placebo or fixed doses of lacosamide 200 , 400 , or 600 mg/d . No back titration was allowed during the trial . The primary efficacy criterion was the change in Likert pain score from baseline to the average over the last 4 weeks of the maintenance phase in the intent-to-treat population . Results The lacosamide 400 mg/d group demonstrated statistically significant improvement in Likert pain score over placebo for the primary efficacy measure . At the end of treatment , 58 % of patients in the lacosamide 400 mg/d treatment group achieved at least a 2 
    Output:
    
The results indicate that pregabalin is established as effective and should be offered for relief of PDN ( Level A ) .
Venlafaxine , duloxetine , amitriptyline , gabapentin , valproate , opioids ( morphine sulfate , tramadol , and oxycodone controlled-release ) , and capsaicin are probably effective and should be considered for treatment of PDN ( Level B ) .
Effective treatments for PDN are available , but many have side effects that limit their usefulness .