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Journal of Pain and Symptom Management Feb 2010Opioids are recommended for control of moderate-to-severe, chronic, malignant, and nonmalignant pain. A controlled-release formulation of the opioid oxymorphone has... (Meta-Analysis)
Meta-Analysis Review
Opioids are recommended for control of moderate-to-severe, chronic, malignant, and nonmalignant pain. A controlled-release formulation of the opioid oxymorphone has recently been launched. The aim of this review was to assess the effectiveness of oxymorphone as an analgesic in chronic pain. A systematic search for published studies of oral oxymorphone in the management of chronic pain was conducted. The studies were evaluated for their internal validity according to standard criteria. They were also evaluated for their external validity and research ethic aspects. A meta-analysis was performed to examine the effect of oxymorphone compared with placebo. Nine studies were evaluated; three were excluded because of low quality. Six controlled studies (duration 2-12 weeks) included a total of 1489 subjects suffering from chronic low back pain, chronic pain from osteoarthritis, and chronic cancer pain. Three of the studies were of high quality and three of medium quality. External validity was assessed to be high, medium, and low (in one, three, and two studies, respectively). The meta-analysis suggests that daily doses of 40-100mg are superior to placebo; however, the estimate (reduction of pain intensity compared with placebo) of the treatment effect is imprecise (95% confidence interval -17.08, -8.69). Limited evidence suggests that oxymorphone is effective for pain control in patients with cancer. No significant differences between oxymorphone and oxycodone at equipotent doses were found. In conclusion, oxymorphone is superior to placebo. There is no evidence that the efficacy of oxymorphone differs from other opioids.
Topics: Analgesics, Opioid; Chronic Disease; Humans; Low Back Pain; Neoplasms; Osteoarthritis; Oxymorphone; Pain; Randomized Controlled Trials as Topic
PubMed: 20152592
DOI: 10.1016/j.jpainsymman.2009.07.010 -
The Journal of Arthroplasty Feb 2024Pain is challenging after recovery from total knee arthroplasty (TKA) and total hip arthroplasty (THA) procedures, and patients often receive prescription opioids....
BACKGROUND
Pain is challenging after recovery from total knee arthroplasty (TKA) and total hip arthroplasty (THA) procedures, and patients often receive prescription opioids. However, opioid consumption by patients remains unclear, and unused opioids may lead to risks including misuse and diversion. The objective of this systematic review and meta-analysis was to compare prescription size versus patient-reported consumption of opioids after discharge following TKA and THA.
METHODS
PubMed and Embase were systematically searched for publications published between 2015 and 2022 on patient-reported consumption of opioids after TKA and THA. The primary outcome was opioid use in oxycodone 5-mg equivalents. Team members independently reviewed studies for screening, inclusion, data extraction, and risk of bias.
RESULTS
Among the 17 included studies (15 TKA and 11 THA), discharge opioid prescribing exceeded consumption for both TKA (88.4 versus 65.0 pills at 6 weeks) and THA (64.0 versus 29.8 pills at 12 weeks). For both TKA and THA, the range of opioids prescribed varied significantly, by 1.6-fold for TKA and 2.8-fold for THA. Most studies reported pain outcomes (89%) and the use of nonopioid medications (72%). Of the 4 studies offering prescribing recommendations, the amounts ranged from 50 to 104 pills for TKA and 30 to 45 pills for THA.
CONCLUSIONS
Opioid prescribing exceeds the amount consumed following TKA and THA. These findings serve as a call to action to tailor prescribing guidelines to how much patients actually consume while emphasizing the use of nonopioid medications to better optimize recovery from surgery.
PubMed: 38336301
DOI: 10.1016/j.arth.2024.01.063 -
The American Journal of Sports Medicine Jun 2017Effective postoperative pain management after shoulder arthroscopy is a critical component to recovery, rehabilitation, and patient satisfaction. (Review)
Review
BACKGROUND
Effective postoperative pain management after shoulder arthroscopy is a critical component to recovery, rehabilitation, and patient satisfaction.
PURPOSE
This systematic review provides a comprehensive overview of level 1 and level 2 evidence regarding postoperative pain management for outpatient arthroscopic shoulder surgery.
STUDY DESIGN
Systematic review.
METHODS
We performed a systematic review of the various modalities reported in the literature for postoperative pain control after outpatient shoulder arthroscopy and analyzed their outcomes. Analgesic regimens reviewed include regional nerve blocks/infusions, subacromial/intra-articular injections or infusions, cryotherapy, and oral medications. Only randomized control trials with level 1 or level 2 evidence that compared 2 or more pain management modalities or placebo were included. We excluded studies without objective measures to quantify postoperative pain within the first postoperative month, subjective pain scale measurements, or narcotic consumption as outcome measures.
RESULTS
A combined total of 40 randomized control trials met our inclusion criteria. Of the 40 included studies, 15 examined nerve blocks, 4 studied oral medication regimens, 12 studied subacromial infusion, 8 compared multiple modalities, and 1 evaluated cryotherapy. Interscalene nerve blocks (ISBs) were found to be the most effective method to control postoperative pain after shoulder arthroscopy. Increasing concentrations, continuous infusions, and patient-controlled methods can be effective for more aggressively controlling pain. Dexamethasone, clonidine, intrabursal oxycodone, and magnesium have all been shown to successfully improve the duration and adequacy of ISBs when used as adjuvants. Oral pregabalin and etoricoxib administered preoperatively have evidence supporting decreased postoperative pain and increased patient satisfaction.
CONCLUSION
On the basis of the evidence in this review, we recommend the use of ISBs as the most effective analgesic for outpatient arthroscopic shoulder surgery.
Topics: Ambulatory Care; Analgesics; Anesthetics, Local; Arthroscopy; Cryotherapy; Humans; Injections, Intra-Articular; Nerve Block; Pain Management; Pain Measurement; Pain, Postoperative; Patient Satisfaction; Randomized Controlled Trials as Topic; Shoulder
PubMed: 27729319
DOI: 10.1177/0363546516667906 -
Palliative Medicine Jul 2011Opioid use in patients with renal impairment can lead to increased adverse effects. Opioids differ in their effect in renal impairment in both efficacy and tolerability.... (Review)
Review
A systematic review of the use of opioid medication for those with moderate to severe cancer pain and renal impairment: a European Palliative Care Research Collaborative opioid guidelines project.
BACKGROUND
Opioid use in patients with renal impairment can lead to increased adverse effects. Opioids differ in their effect in renal impairment in both efficacy and tolerability. This systematic literature review forms the basis of guidelines for opioid use in renal impairment and cancer pain as part of the European Palliative Care Research Collaborative's opioid guidelines project.
OBJECTIVE
The objective of this study was to identify and assess the quality of evidence for the safe and effective use of opioids for the relief of cancer pain in patients with renal impairment and to produce guidelines.
SEARCH STRATEGY
The Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, MedLine, EMBASE and CINAHL were systematically searched in addition to hand searching of relevant journals.
SELECTION CRITERIA
Studies were included if they reported a clinical outcome relevant to the use of selected opioids in cancer-related pain and renal impairment. The selected opioids were morphine, diamorphine, codeine, dextropropoxyphene, dihydrocodeine, oxycodone, hydromorphone, buprenorphine, tramadol, alfentanil, fentanyl, sufentanil, remifentanil, pethidine and methadone. No direct comparator was required for inclusion. Studies assessing the long-term efficacy of opioids during dialysis were excluded.
DATA COLLECTION AND ANALYSIS
This is a narrative systematic review and no meta-analysis was performed. The Grading of RECOMMENDATIONS Assessment, Development and Evaluation (GRADE) approach was used to assess the quality of the studies and to formulate guidelines.
MAIN RESULTS
Fifteen original articles were identified. Eight prospective and seven retrospective clinical studies were identified but no randomized controlled trials. No results were found for diamorphine, codeine, dihydrocodeine, buprenorphine, tramadol, dextropropoxyphene, methadone or remifentanil.
CONCLUSIONS
All of the studies identified have a significant risk of bias inherent in the study methodology and there is additional significant risk of publication bias. Overall evidence is of very low quality. The direct clinical evidence in cancer-related pain and renal impairment is insufficient to allow formulation of guidelines but is suggestive of significant differences in risk between opioids.
RECOMMENDATIONS
RECOMMENDATIONS regarding opioid use in renal impairment and cancer pain are made on the basis of pharmacokinetic data, extrapolation from non-cancer pain studies and from clinical experience. The risk of opioid use in renal impairment is stratified according to the activity of opioid metabolites, potential for accumulation and reports of successful or harmful use. Fentanyl, alfentanil and methadone are identified, with caveats, as the least likely to cause harm when used appropriately. Morphine may be associated with toxicity in patients with renal impairment. Unwanted side effects with morphine may be satisfactorily dealt with by either increasing the dosing interval or reducing the 24 hour dose or by switching to an alternative opioid.
Topics: Analgesics, Opioid; Clinical Trials as Topic; Europe; Humans; Neoplasms; Pain; Pain Measurement; Practice Guidelines as Topic; Renal Insufficiency; Severity of Illness Index
PubMed: 21708859
DOI: 10.1177/0269216311406313 -
American Journal of Public Health Aug 2014We review evidence of determinants contributing to increased opioid-related mortality in the United States and Canada between 1990 and 2013. We identified 17... (Review)
Review
We review evidence of determinants contributing to increased opioid-related mortality in the United States and Canada between 1990 and 2013. We identified 17 determinants of opioid-related mortality and mortality increases that we classified into 3 categories: prescriber behavior, user behavior and characteristics, and environmental and systemic determinants. These determinants operate independently but interact in complex ways that vary according to geography and population, making generalization from single studies inadvisable. Researchers in this area face significant methodological difficulties; most of the studies in our review were ecological or observational and lacked control groups or adjustment for confounding factors; thus, causal inferences are difficult. Preventing additional opioid-related mortality will likely require interventions that address multiple determinants and are tailored to specific locations and populations.
Topics: Analgesics, Opioid; Canada; Humans; Methadone; Noscapine; Opioid-Related Disorders; Oxycodone; Practice Patterns, Physicians'; Risk Factors; Socioeconomic Factors; United States
PubMed: 24922138
DOI: 10.2105/AJPH.2014.301966 -
Drugs & Aging Jun 2017There is substantial evidence that the use of opioids increases the risk of adverse outcomes such as delirium, but whether this risk differs between the various opioids... (Review)
Review
OBJECTIVE
There is substantial evidence that the use of opioids increases the risk of adverse outcomes such as delirium, but whether this risk differs between the various opioids remains controversial. In this systematic review, we evaluate and discuss possible differences in the risk of delirium from the use of various types of opioids in older patients.
METHODS
We performed a search in MEDLINE by combining search terms on delirium and opioids. A specific search filter for use in geriatric medicine was used. Quality was scored according to the quality assessment for cohort studies of the Dutch Cochrane Institute.
RESULTS
Six studies were included, all performed in surgical departments and all observational. No study was rated high quality, one was rated moderate quality, and five were rated low quality. Information about dose, route, and timing of administration of the opioid was frequently missing. Pain and other important risk factors of delirium were often not taken into account. Use of tramadol or meperidine was associated with an increased risk of delirium, whereas the use of morphine, fentanyl, oxycodone, and codeine were not, when compared with no opioid. Meperidine was also associated with an increased risk of delirium compared with other opioids, whereas tramadol was not. The risk of delirium appeared to be lower with hydromorphone or fentanyl, compared with other opioids. Numbers used for comparisons were small.
CONCLUSION
Some data suggest that meperidine may lead to a higher perioperative risk for delirium; however, high-quality studies that compare different opioids are lacking. Further comparative research is needed.
Topics: Aged; Analgesics, Opioid; Delirium; Humans; Hydromorphone; Meperidine; Morphine; Oxycodone; Pain; Pain Measurement; Risk Factors; Tramadol
PubMed: 28405945
DOI: 10.1007/s40266-017-0455-9 -
Schmerz (Berlin, Germany) Feb 2015The efficacy, tolerability and safety of opioid therapy in chronic osteoarthritis (OA) pain is under debate. We updated a Cochrane systematic review on the efficacy and... (Comparative Study)
Comparative Study Review
[Opioids in chronic osteoarthritis pain. A systematic review and meta-analysis of efficacy, tolerability and safety in randomized placebo-controlled studies of at least 4 weeks duration].
BACKGROUND
The efficacy, tolerability and safety of opioid therapy in chronic osteoarthritis (OA) pain is under debate. We updated a Cochrane systematic review on the efficacy and safety of opioids in chronic OA pain published in 2009.
METHODS
We screened MEDLINE, Scopus and the Cochrane Central Register of Controlled Trials (CENTRAL) up until October 2013, as well as reference sections of original studies and systematic reviews of randomized controlled trials (RCTs) of opioids in chronic osteoarthritis (OA) pain. We included double-blind randomized placebo-controlled studies lasting ≥ 4 weeks. Using a random effects model, absolute risk differences (RD) were calculated for categorical data and standardized mean differences (SMD) for continuous variables.
RESULTS
We included 20 RCTs with 33 treatment arms and 8545 participants. Median study duration was 12 (4-24) weeks. Oxycodone and tramadol were each tested in six studies; buprenorphine, hydromorphone, morphine and tapentadol each in two studies and codeine, fentanyl and oxymorphone in one study each. Results are reported with 95 % confidence intervals (CIs). Opioids were superior to placebo in reducing pain intensity (SMD - 0.22 [- 0.28, - 0.17], p < 0.00001; 16 studies with 6743 participants). Opioids were not superior to placebo in 50 % pain reduction (RD - 0.00 [- 0.07, 0.07], p = 0.96; two studies with 2684 participants). Opioids were superior to placebo in terms of reports of much or very much global improvement (RD 0.13 [0.05, 0.21], p = 0.002; three studies with 2251 participants). Opioids were superior to placebo in improving physical functioning (SMD - 0.22 [- 0.28, - 0.17], p < 0.00001; 14 studies with 5887 participants). Patients dropped out more frequently with opioids than with placebo (RD 0.17 [0.14, 0.21], p < 0.00001; 15 studies with 6834 participants; number needed to harm 5 [4-6]. There was no significant difference between opioids and placebo in the frequency of serious adverse events (SAE) or deaths over the respective observation periods.
CONCLUSION
Opioids were superior to placebo in terms of efficacy and inferior in terms of tolerability. The effect sizes of average reduction in pain intensity and physical disability were small. Opioids and placebo did not differ in terms of safety. The conclusion on the safety of opioids compared to placebo is limited by the low number of SAE and deaths. Short-term opioid therapy may be considered in selected chronic OA pain patients. No current evidence-based guideline recommends opioids as first-line treatment option for chronic OA pain. To provide superior evidence for future treatment guidelines, RCTs must directly compare existing pharmacological and nonpharmacological therapies and administer these in various combinations and sequences. The English full-text version of this article is freely available at SpringerLink (under "Supplemental").
Topics: Adult; Analgesics, Opioid; Chronic Pain; Double-Blind Method; Evidence-Based Medicine; Humans; Long-Term Care; Osteoarthritis; Pain Measurement; Randomized Controlled Trials as Topic; Treatment Outcome
PubMed: 25376547
DOI: 10.1007/s00482-014-1451-1 -
PM & R : the Journal of Injury,... Apr 2011To develop a scientifically sound and clinically relevant evidence-based guideline for the treatment of painful diabetic neuropathy (PDN). (Review)
Review
Evidence-based guideline: Treatment of painful diabetic neuropathy: report of the American Academy of Neurology, the American Association of Neuromuscular and Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation.
OBJECTIVE
To develop a scientifically sound and clinically relevant evidence-based guideline for the treatment of painful diabetic neuropathy (PDN).
METHODS
We performed a systematic review of the literature from 1960 to August 2008 and classified the studies according to the American Academy of Neurology classification of evidence scheme for a therapeutic article, and recommendations were linked to the strength of the evidence. The basic question asked was: "What is the efficacy of a given treatment (pharmacological: anticonvulsants, antidepressants, opioids, others; and non-pharmacological: electrical stimulation, magnetic field treatment, low-intensity laser treatment, Reiki massage, others) to reduce pain and improve physical function and quality of life (QOL) in patients with PDN?"
RESULTS AND RECOMMENDATIONS
Pregabalin is established as effective and should be offered for relief of PDN (Level A). Venlafaxine, duloxetine, amitriptyline, gabapentin, valproate, opioids (morphine sulphate, tramadol, and oxycodone controlled-release), and capsaicin are probably effective and should be considered for treatment of PDN (Level B). Other treatments have less robust evidence or the evidence is negative. Effective treatments for PDN are available, but many have side effects that limit their usefulness, and few studies have sufficient information on treatment effects on function and QOL.
Topics: Academies and Institutes; Diabetic Nephropathies; Electrodiagnosis; Evidence-Based Medicine; Humans; Neurology; Pain; Physical Therapy Specialty; Practice Guidelines as Topic; Societies, Medical; United States
PubMed: 21497321
DOI: 10.1016/j.pmrj.2011.03.008 -
The Cochrane Database of Systematic... Jun 2013Combining two different analgesics in fixed doses in a single tablet can provide better pain relief than either drug alone in acute pain. This appears to be broadly true... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Combining two different analgesics in fixed doses in a single tablet can provide better pain relief than either drug alone in acute pain. This appears to be broadly true across a range of different drug combinations, in postoperative pain and migraine headache. Fixed-dose combinations of ibuprofen and oxycodone are available, and the drugs may be separately used in combination in some acute pain situations.
OBJECTIVES
To assess the analgesic efficacy and adverse effects of a single oral dose of ibuprofen plus oxycodone for moderate to severe postoperative pain.
SEARCH METHODS
We searched the Cochrane Central Register of Controlled Trials, (CENTRAL), on The Cochrane Library, (Issue 4 of 12, 2013), MEDLINE (1950 to 21st May 2013), EMBASE (1974 to 21st May 2013), the Oxford Pain Database, ClinicalTrials.gov, and reference lists of articles.
SELECTION CRITERIA
Randomised, double-blind clinical trials of single dose, oral ibuprofen plus oxycodone compared with placebo or the same dose of ibuprofen alone for acute postoperative pain in adults.
DATA COLLECTION AND ANALYSIS
Two review authors independently considered trials for inclusion in the review, assessed quality, and extracted data. We used the area under the pain relief versus time curve to derive the proportion of participants prescribed ibuprofen plus oxycodone, ibuprofen alone, oxycodone alone, or placebo with at least 50% pain relief over six hours, using validated equations. We calculated relative risk (RR) and number needed to treat to benefit (NNT). We used information on use of rescue medication to calculate the proportion of participants requiring rescue medication and the weighted mean of the median time to use. We also collected information on adverse events.
MAIN RESULTS
Searches identified three studies involving 1202 participants. All examined the same dose combination. Included studies provided data from 603 participants for the comparison of ibuprofen 400 mg + oxycodone 5 mg with placebo, 717 participants for the comparison of ibuprofen 400 mg + oxycodone 5 mg with ibuprofen 400 mg alone, and 471 participants for the comparison of ibuprofen 400 mg + oxycodone 5 mg with oxycodone 5 mg alone.The proportion of participants achieving at least 50% pain relief over 6 hours was 60% with ibuprofen 400 mg + oxycodone 5 mg and 17% with placebo, giving an NNT of 2.3 (2.0 to 2.8). For ibuprofen 400 mg alone the proportion was 50%, producing no significant difference between ibuprofen 400 mg + oxycodone 5 mg and ibuprofen 400 mg alone. For oxycodone 5 mg alone the proportion was 23%, giving an NNT for ibuprofen 400 mg + oxycodone 5 mg compared with oxycodone alone of 2.9 (2.3 to 4.0).Ibuprofen + oxycodone resulted in longer times to remedication than with placebo. The median time to use of rescue medication was more than 5 hours for ibuprofen 400 mg + oxycodone 5 mg, and 2.3 hours or less with placebo. Fewer participants needed rescue medication with ibuprofen + oxycodone combination than with placebo or ibuprofen alone. The proportion was 40% with ibuprofen 400 mg + oxycodone 5 mg, 83% with placebo, 53% with ibuprofen alone, and 83% with oxycodone alone, giving NNT to prevent one patient needing rescue medication of 2.4 (2.0 to 2.9), 11 (6.1 to 56), and 2.6 (2.1 to 3.4) for comparisons of ibuprofen 400 mg + oxycodone 5 mg with placebo, ibuprofen alone, and oxycodone alone, respectively.The proportion of participants experiencing one or more adverse events was 25% with ibuprofen 400 mg + oxycodone 5 mg, 25% with placebo, 26% with ibuprofen alone, and 35% with oxycodone alone; they were not significantly different. Serious adverse events were reported only after abdominal surgery 6/169 with the combination, 1/175 with ibuprofen alone, 3/52 with oxycodone alone, and 1/60 with placebo. Withdrawals for reasons other than lack of efficacy were fewer than 5% and balanced across treatment arms.
AUTHORS' CONCLUSIONS
The combination of ibuprofen 400mg + oxycodone 5mg provided analgesia for longer than oxycodone alone, but not ibuprofen alone (at the same dose). There was also a smaller chance of needing additional analgesia over about eight hours, and with no greater chance of experiencing an adverse event.
Topics: Acute Pain; Administration, Oral; Adult; Analgesics, Non-Narcotic; Analgesics, Opioid; Drug Combinations; Humans; Ibuprofen; Oxycodone; Pain, Postoperative; Randomized Controlled Trials as Topic
PubMed: 23801549
DOI: 10.1002/14651858.CD010289.pub2 -
Schmerz (Berlin, Germany) Feb 2015The efficacy and safety of opioid therapy in chronic neuropathic pain (CNP) is under debate. We updated a recent Cochrane systematic review on the efficacy, tolerability... (Comparative Study)
Comparative Study Meta-Analysis Review
[Opioids in chronic neuropathic pain. A systematic review and meta-analysis of efficacy, tolerability and safety in randomized placebo-controlled studies of at least 4 weeks duration].
BACKGROUND
The efficacy and safety of opioid therapy in chronic neuropathic pain (CNP) is under debate. We updated a recent Cochrane systematic review on the efficacy, tolerability and safety of opioids in CNP.
METHODS
We screened MEDLINE, Scopus and the Cochrane Central Register of Controlled Trials (CENTRAL) up until October 2013, as well as the reference sections of original studies and systematic reviews of randomized controlled trials (RCTs) of opioids in CNP. We included double-blind randomized placebo-controlled studies of at least 4 weeks duration. Using a random effects model, absolute risk differences (RD) were calculated for categorical data and standardized mean differences (SMD) for continuous variables.
RESULTS
We included 12 RCTs with 1192 participants. The included diagnostic entities were painful diabetic neuropathy (four studies), postherpetic neuralgia (three studies), mixed polyneuropathic pain (two studies), and lumbar root, spinal cord injury and postamputation pain (one study each). Mean study duration was 6 (4-12) weeks. Four studies tested morphine, three studies tramadol, two studies oxycodone and one study tapentadol. These are the pooled results of studies with a parallel or cross-over design: opioids were superior to placebo in reducing pain intensity (SMD - 0.64 [95 % confidence interval, CI - 0.81, - 0.46], p < 0.0001; 11 studies with 1040 participants). Opioids were not superior to placebo in 50 % pain reduction (RD 0.16 [95 % CI - 0.04, 0.35], p = 0.11; one study with 93 participants). Opioids were not superior to placebo in reports of much or very much improved pain (RD 0.17 [95 % CI - 0.01, 0.36], p = 0.07; one study with 53 participants). Opioids were superior to placebo in improving physical functioning (SMD - 0.28 [95 % CI - 0.43, - 0.13], p < 0.0001; seven studies with 680 participants). Patients dropped out less frequently due to lack of efficacy with opioids than with placebo (RD - 0.07 [95 % CI - 0.13, - 0.02], p = 0.008; six studies with 656 participants). Patients dropped out due to adverse events more frequently with opioids than with placebo (RD 0.08 [95 % CI 0.05, 0.12], p < 0.0001; ten studies with 1018 participants; number needed to harm 11 [95 % CI 8-17]). There was no significant difference between opioids and placebo in terms of the frequency of serious adverse events (SAE) or deaths.
CONCLUSION
In short-term studies (4-12 weeks) in CNP, opioids were superior to placebo in terms of efficacy and inferior in terms of tolerability. Opioids and placebo did not differ in terms of safety. The conclusion relating to the safety of opioids compared to placebo in CNP is limited by the low number of SAE and deaths. Short-term opioid therapy may be considered in selected CNP patients. The English full-text version of this article is freely available at SpringerLink (under "Supplementary Material").
Topics: Analgesics, Opioid; Chronic Pain; Humans; Long-Term Care; Neuralgia; Pain Measurement; Randomized Controlled Trials as Topic; Treatment Outcome
PubMed: 25376548
DOI: 10.1007/s00482-014-1455-x