Is Caffeine Addictive?—A Review of the Literature The American Journal of Drug and Alcohol Abuse, 32:493-502, 2006 Informa Healthcare ISSN: 0095-2990 print /1097-9891 online DOI: 10.1080/00952990600918965 Is Caffeine Addictive?—A Review of the Literature Sally Satel, M.D.*1 1Oasis Clinic, American Enterprise Institute. *Correspondence: Sally Satel, M.D., 1150 17th St. NW, Washington, D
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Ken470 520.527Advance Access publication 24 December 2008 Analgesic effects of treatments for non-specific low back pain:a meta-analysis of placebo-controlled randomized trials L. A. C. Machado1, S. J. Kamper1, R. D. Herbert1, C. G. Maher1 and J. H. McAuley2 Objective. Estimates of treatment effects reported in placebo-controlled randomized trials are less subject to bias than those estimatesprovided by other study designs. The objective of this meta-analysis was to estimate the analgesic effects of treatments for non-specific lowback pain reported in placebo-controlled randomized trials.
Methods. Medline, Embase, Cinahl, PsychInfo and Cochrane Central Register of Controlled Trials databases were searched for eligible trialsfrom earliest records to November 2006. Continuous pain outcomes were converted to a common 0–100 scale and pooled using a randomeffects model.
Results. A total of 76 trials reporting on 34 treatments were included. Fifty percent of the investigated treatments had statistically significanteffects, but for most the effects were small or moderate: 47% had point estimates of effects of <10 points on the 100-point scale, 38% hadpoint estimates from 10 to 20 points and 15% had point estimates of >20 points. Treatments reported to have large effects (>20 points) hadbeen investigated only in a single trial.
Conclusions. This meta-analysis revealed that the analgesic effects of many treatments for non-specific low back pain are small and thatthey do not differ in populations with acute or chronic symptoms.
KEY WORDS: Meta-analysis, Randomized-controlled trial, Treatment efficacy, Low back pain, Placebo effect.
systematic review and meta-analysis of placebo-controlled rando-mized trials investigating the effects of treatments for NSLBP.
Low back pain is a highly prevalent health problem that isassociated with enormous costs worldwide [1–3]. In developedcountries, episodes of back pain are a leading cause of work absence, accounting for over 25% of all conditions involving days away from work [4, 5]. About 90% of the patients with low backpain will receive the diagnosis ‘non-specific low back pain’ The electronic databases Medline, Embase, Cinahl, PsychInfo and (NSLBP), a term that signifies that no specific pathology or the Cochrane Central Register of Controlled Trials were searched disease process has been identified by the clinician. Although pain from the earliest record to November 2006 for placebo-controlled improves rapidly in the first month with a typical episode of randomized trials of treatments for NSLBP. Our search strategy NSLBP, low levels of pain may continue for many months .
followed the recommendations of the Cochrane Back Review The number of studies investigating the effects of treatments for Group . The results were combined with the terms ‘placebo’, patients with NSLBP has increased dramatically in the past ‘sham’, ‘attention-control’ or ‘minimal intervention’. We also decade. Some of these studies compare outcomes in a treated searched cited references of relevant trial reports and reviews for group with outcomes of a group that is given placebo treatment or sham treatment. The use of a placebo is generally considered to be Eligible studies were randomized controlled trials comparing a good design feature because it controls for placebo effects and, treatments for NSLBP against placebo. To be included, they must more generally, for changes in patient behaviour caused by have reported a continuous measure of pain. Studies in which knowledge of allocation . The provision of a placebo may also participants presented with radicular syndrome, cauda equina enable better control of other sources of bias in clinical trials, such syndrome, infection, neoplasm, fracture, inflammatory disease, as measurement bias, treatment non-compliance and loss to pregnancy or spinal surgery in the past 12 months were excluded, as were primary prevention studies. Trials in which the placebo The ability of placebos to control for bias in clinical research is intervention was a contemporary treatment (e.g. an educational closely linked to the facilitation of blinding . In a recent meta- epidemiological study, the lack of blinding was associated with a25% over-estimation of treatment effects when these effects were measured in terms of subjective outcomes, such as pain [odds ratio Two independent reviewers extracted data using a standard form.
(OR) 0.75; 95% CI 0.61, 0.93] . Thus, at least from an A third reviewer extracted data for non-English studies. Trial explanatory perspective, placebo-controlled trials may provide the quality was assessed using the PEDro scale , an 11-item quality least biased estimates of the analgesic effects of treatments.
checklist. The full scale criteria can be viewed at To our knowledge there have not been any systematic reviews pedro.fhs.usyd.edu.au/scale_item.html.
focusing on the analgesic effects of treatments estimated by resolved by discussion and consensus. Trials were included in placebo-controlled trials on NSLBP. Thus, we performed a the analysis regardless of their quality ratings. Data on continuouspain outcomes are often reported at several time points. We choseto extract data from the first assessment after the end of the 1The George Institute for International Health and 2Faculty of Health Sciences, The therapy. This timing was decided a priori because it was University of Sydney, Sydney, Australia.
considered the time-point where the largest analgesic effects Submitted 30 June 2008; revised version accepted 20 November 2008.
For simplicity, trials comparing multiple treatments of diverse Correspondence to: C. G. Maher, The George Institute for International Health, PO Box M201, Missenden Rd, Sydney, NSW 2050, Australia.
nature against the same placebo had each of their comparisons treated as an individual trial. However, when a single trial ß The Author 2008. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: firstname.lastname@example.org Analgesic effects of treatments for low back pain compared more than one treatment of the same type (e.g. differentdosages of the same drug) to the same placebo group, only one comparison per trial was entered into any analysis. In that case, the preferred studies were those in which the experimental group consisted of a single treatment as opposed to combinations oftreatments. If there was more than one group receiving single treatments, one was selected at random.
Where necessary, pain scores were re-scaled to a 0- to 100-point scale. For each trial, wherever possible, the size of the treatment effect was estimated by subtracting the mean pain in the treatment group from the mean pain in the control group. Methods described in the Cochrane Handbook  were used to calculate the variance of the estimate. Where there were insufficient data,the S.D. for assessments at baseline or the pooled S.D. of trials reporting on the same intervention was used . The same procedure was used in one trial reporting implausible S.D.S .
Where more than one trial estimated the effect of a particular treatment, a random effects model was used to obtain a pooled estimate of the effect (weighted mean difference, WMD) of thattreatment. We used MIX (version 1.6) for the analyses .
FIG. 1. Selection of studies for inclusion.
A pre-specified secondary analysis was performed to evaluate the efficacy of treatments in populations with distinct duration ofsymptoms. Acute symptoms were defined as those present for <6 TABLE 1. Contemporary treatments referred to as placebo treatments in trials of weeks, sub-acute symptoms as those present from 6 weeks to 3 months, and chronic symptoms as those present for over 3 months. Trials not reporting the duration of the symptoms, or having a mix of patients with acute and chronic symptoms, were not included in the secondary analysis. To judge the magnitude of treatment effects (represented by the absolute differences between experimental and placebo groups at follow-up), we used the Superficial needling at non-acupuncture points definitions of the American College of Physicians and the American Pain Society, as follows: large treatment effect (>20 points), moderate treatment effect (10–20 points) and small treatment effect (<10 points) .
Superficial needling at non-acupuncture points Exercises and simulated osteopathic techniques Superficial needling at non-acupuncture points Figure 1 describes the process of study selection. A total of 1031 Superficial needling at non-acupuncture points and papers were identified by the search strategy and screened for eligibility, of which 946 failed to meet the inclusion criteria. In 21 Low-dose lignocaine injection, non-forceful manipulation, studies the reason for ineligibility was that the trial employed Acupuncture needling without electrical stimulation a placebo that is a contemporary treatment for NSLBP [19–39].
Table 1 lists the treatments used as placebos in these trials. Of the 85 eligible trials, 9 were excluded from the analysis because they provided insufficient data to estimate treatment effects [40–48].
Education by didactic presentation and information sheet Low-force spinal manipulation and soft-tissue massage Thus, 76 trials reporting on 34 different treatments were included Acupuncture needling without electrical stimulation and SWD: shortwave diathermy; US: ultrasound; TENS: transcutaneous electrical nerve Table 2 describes the characteristics of the included trials. Fromthe 76 trials included, 81 comparisons against placebo were pragmatic physiotherapy [62, 64] and the provision of educational considered. Muscle relaxants were tested in the largest number of material . Concurrent therapies were allowed in 36 trials, trials (nine trials), while NSAIDs were tested on the largest which were mostly rescue medication or the continuation of number of participants (1349 participants). Trial quality was previous treatment regimens. Because of the different duration of highly variable; individual items of the quality checklist are treatments, we had to use various time-points for data extraction, described in the Appendix (see supplementary data available at which ranged from 5 min after the intervention in a trial of Rheumatology Online). Two trials investigating the effects of neuroreflexotherapy to 52 weeks after intervention in a trial of exercise  and spinal manipulative therapy (SMT)  scored intradiscal steroid injections (ISIs) (Table 2).
3 points on the PEDro scale, a score that has been consideredthe cut-off for low-quality trials in previous reviews [124, 125].
In 10 trials, the treatment under investigation was delivered in addition to baseline care provided to both the experimental and Seventeen of the investigated treatments (50%) had statistically the placebo groups. Baseline treatments included exercise pro- significant effects compared with placebo (Fig. 2). Point grammes [82, 103, 104, 107, 121], heat therapy , NSAIDs , estimates of the effects were small for 16 treatments (colchicine, TABLE 2. Characteristics of included trials aNumber of comparisons against placebo. bTotal number of participants in the experimental and placebo groups for whom data were available at the time-point for data extraction. ATP: adenosine triphosphate; ISIs: Intradiscal steroid injections; NMDA: N-methyl-D-aspartate; PTIT: percutaneous thermocoagulation intradiscal techniques; RF: radiofrequency; SMT: Spinal manipulative therapy;TENS: transcutaneous electrical nerve stimulation.
N-methyl-D-aspartate antagonists, shortwave, ISIs, percutaneous NSLBP are small. Large effects were only observed in single thermocoagulation intradiscal techniques, radiotherapy, traction, small trials. Additionally, treatment effects do not differ in physiotherapy, prolotherapy, exercise, anti-depressants, behav- populations with acute or chronic NSLBP.
ioural, adenosine triphosphate, SMT, NSAIDs and magnets), Interestingly, treatment recommendations from recent clinical moderate for 13 treatments (analgesics, radiofrequency denerva- guidelines do not align with the results of this meta-analysis. For tion, herbal medicines, facet injections, laser, massage, muscle example, five of the treatments recommended in the 2007 relaxants, anti-convulsants, back school, nerve blocks, transcuta- guideline of the American Pain Society (anti-depressants, SMT, neous electrical nerve stimulation, heat wrap therapy and exercise, acupuncture, behavioural therapies)  were shown in acupuncture) and large for five treatments (neuroreflexotherapy, this review to be not more effective than placebo. Inconsistencies vitamin B12, infrared, immunoglobulins and electroacupuncture).
like these are not surprising because, unlike our approach, However, with the possible exception of heat wrap therapy, the CIs guideline committees also consider the results from trials with a about moderate estimates were not narrow enough to rule out no-treatment control and trials comparing two active treatments small effects. Additionally, all five large estimates were based on when providing their recommendations. The findings of these just one small- or moderate-sized study. A post hoc analysis latter types of trials (known as pragmatic trials) are generally excluding the two low-quality trials [68, 115] produced even smaller considered more useful for clinicians because their design analgesic effects for both exercise (pooled effect À1.7; 95% CI replicates more closely what happens in everyday clinical practice.
À8.2, 4.8) and SMT (pooled effect À1.4; 95% CI À9.4, 6.6).
However, in some pragmatic trials the interpretation of findings We sought to determine if the effects of treatment, compared may be more difficult than in placebo-controlled trials. For with placebo, varied with the duration of symptoms (acute, sub- example, a null result in a trial comparing two active treatments of acute or chronic). There were no studies reporting exclusively on unknown efficacy, often observed in the NSLBP literature, may sub-acute NSLBP, so trials having a mix of patients with acute mean that the treatments are equally effective or equally and sub-acute symptoms (<3 months) or with sub-acute and ineffective since they may not be superior to a placebo.
chronic symptoms (>6 weeks) were treated in our secondary During the conduct of the present meta-analysis, another study analysis as acute or chronic NSLBP, respectively (Table 2).
with a similar aim was published by Keller et al. . Despite the Figure 3 shows the analgesic efficacy, compared with placebo, of similar aims of the two meta-analyses, their methods and four treatments investigated in both acute and chronic popula- execution were fundamentally different. First, the search in the tions. There was no evidence of substantial differences in effects Keller review was less comprehensive than ours: the review did not include trials reporting on 27 treatments included in our review,including some commonly prescribed treatments for NSLBP, suchas analgesics and anti-depressants. Second, the Keller review included trials with a no-treatment control, rather than restricting A meta-analysis of 76 placebo-controlled randomized trials the analysis to trials with a placebo control. Trials with a revealed that the analgesic effects of many treatments for no-treatment control have a higher risk of bias and so may Analgesic effects of treatments for low back pain FIG. 2. Analgesic efficacy of treatments for NSLBP of any duration. Squares represent pooled estimates of random effects (multiple trials) or means (single trials). Error barsare 95% CIs. Negative values favour treatment. In parentheses: number of trials; total number of participants. The dotted lines define the magnitude of effects: large(>20 U); moderate (10–20 U); small (<20 U). ATP: adenosine triphosphate; ISIs: Intradiscal steroid injections; NMDA: N-methyl-D-aspartate. PTIT: percutaneousthermocoagulation intradiscal techniques; RF: radiofrequency; SMT: Spinal manipulative therapy; TENS: transcutaneous electrical nerve stimulation; provide overly optimistic estimates of treatment effects. Given The opposite problem can also arise in placebo-controlled trials: these differences, we believe the present meta-analysis provides a some placebos may lack credibility, which could cause an over- more robust evaluation of the analgesic effects of treatments for estimation of treatment effects. Unfortunately, trial reports usually contain insufficient information to judge whether this is Despite the greater control of bias provided by the use of a a problem , so we could not exclude trials using placebos that placebo control in clinical trials, the use of placebos in trials are not credible. As a consequence it is possible that our estimates evaluating non-pharmaceutical treatments for NSLBP has been of the effects of treatments were exaggerated. It would seem contentious. Much of the debate does not relate to ethical unlikely, therefore, that our finding of small effects of treatments issues, but to problems encountered during the design of proper for NSLBP is due to the inadequate design of placebo in placebo- placebos for these trials. The distinction between placebo effects and specific treatment effects may be ill-defined in trials of non- Some authors have argued that the small effects of treatments pharmaceutical treatments. This problem arises, in part, because for acute NSLBP are a consequence of the favourable natural there is often not a clear understanding of the mechanisms history of acute NSLBP. The theory is that, at the conclusion of underlying some non-pharmaceutical treatments . Thus, the treatment in trials, control groups have improved substantially selection of a placebo for these trials generally requires consider- and so there is not ‘room’ for large treatment effects. To evaluate able thought to ensure that the placebo intervention does not share this argument we examined the baseline and follow-up scores from some of the specific therapeutic components of the experimental the acute trials included in the present meta-analysis. Three trials intervention. This issue is more of a concern when placebos are [64, 73, 85] did not report sufficient baseline data and were not designed to resemble the experimental intervention .
considered. In 18 trials [49, 72, 78, 84, 86–91, 95–97, 114, 115, 117, In some placebo-controlled trials, the placebo treatment is 120, 121] mean pain levels at baseline were 62.1 (S.D. 16.5) points actually used in clinical practice as a treatment. Examples are in the treatment group and 61.5 (S.D. 15.9) points in the placebo educational booklets [23, 28], massage  and exercises [25, 27, group. At follow-up mean pain levels were 29.5 (S.D. 13.2) points 36]. In this meta-analysis, we excluded trials using a placebo in the treatment group and 39.6 (S.D. 17.1) points in the placebo consisting of a contemporary treatment. We took this approach to group. This indicates that there is scope for treatment effects (i.e.
minimize the possibility of under-estimation of treatment effects.
mean between-group differences) as large as 40 points to be FIG. 3. Analgesic efficacy, compared with placebo, of treatments for acute and chronic non-specific low back pain. Squares represent pooled estimates of random effects(multiple trials) or means (single trials). Error bars are 95% CIs. Negative values favour treatment. In parentheses: number of trials; total number of participants. SMT:Spinal manipulative therapy. TENS: transcutaneous electrical nerve stimulation.
demonstrated in trials of NSLBP. Thus, the theory that there is no of all treatments for NSLBP that have been tested against placebo.
‘room’ for trials to show large effects of treatments for acute We used a comprehensive search strategy to identify potentially NSLBP does not seem consistent with the data. Given the mean eligible trials, in contrast to other reviews that used previously baseline pain observed in the present meta-analysis, on average, a published systematic reviews as the primary source of data [126, 10-point difference in pain between treatment and placebo groups 136, 137]. Additionally, we excluded placebo-controlled trials in is equivalent to a 16% difference between groups in improvement which the choice of placebo was inappropriate. One potential limitation of the present meta-analysis is the investigation of just Another argument used to explain the small treatment effects one outcome. The outcome of pain was chosen because pain relief found in the NSLBP literature is that most trial samples are is ranked by patients as one of the most important components for conducted on samples from clinically heterogeneous populations.
the satisfactory management of low back pain and it is often the It is possible that specific treatments have large treatment effects original motivation for seeking care from a health practitioner on specific subgroups of patients with NSLBP [128, 129].
, and because most interventions appear to produce consis- However, the evidence of a differential response of identifiable tently greater reductions in pain than in other outcomes.
subgroups in the NSLBP literature is contradictory, as some The available evidence from placebo-controlled trials shows authors report a differential response of subgroups [130–132] only small to moderate treatment effects, over and above placebo, for many interventions that are currently used in the management The small effects found in this meta-analysis might also be of NSLBP. There seems to be a considerable scope for treatments attributed to the choice of outcome measure; i.e. reduction in pain.
for NSLBP to show large treatment effects but how this can be It could be argued that pain is not the most appropriate outcome to make a judgement on the efficacy of treatments that aredesigned to improve other outcomes, such as function or quality of life. However, we feel it is unlikely that an examination of otheroutcomes would produce meaningfully different conclusions to The average effects of treatments for NSLBP are not much greater those in the current meta-analysis because, in previous reviews, pain has consistently shown larger responses to treatment than There is a considerable scope for large treatment effects to be other outcomes for NSLBP [126, 135]. For example, in a previous meta-analysis on the effects of exercise therapy , the pooledeffect of exercise for chronic NSLBP was, at short-term follow-up, Disclosure statement: The authors have declared no conflicts of 7.3 points on a 100-point scale (95% CI 3.7, 10.9) for pain outcomes, and only 2.5 points on a 100-point scale (95% CI 1.0,3.9) for functional outcomes. A similar pattern was observed forintermediate- and long-term follow-ups .
Our meta-analysis has a number of strengths. First, this is the first meta-analysis to provide the estimates of true treatment effects Supplementary data are available at Rheumatology Online.
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- Doctor, “ como y me hincho”. - Ahá. - Y tengo gases. - Ahá. - Y todo el abdomen me hace ruido. - Ahá - Además tengo problemas para ir de cuerpo. Soy muy estreñida. Aunque - ¿Y qué más? - Bueno, siento pesadez luego de comer, aunque no siempre. - Ahá. - Y a veces repito la comida. - ¿Algo más???? - Me duele el hígado, y la cabeza, a veces también l