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Reanalysis of research raises wider questions1
Reanalysis of primary study data on paroxetine prescribing for adolescents has shown increased harm and no apparent clinical benefit. This shows that the conclusions of the original research have to be interpreted differently, raising significant questions with relevance for clinical practice and research ethics.
The Restoring Invisible and Abandoned Trials (RIAT) initiative examined and reanalysed data from Study 329, a double-blind, randomised placebo-controlled trial in 12 US academic psychiatry centres in the 1990s.
In the study, 275 adolescents with major depression of at least eight weeks received paroxetine, imipramine or placebo, and paroxetine was described as ‘generally well tolerated and effective’.
The RIAT analysis shows that neither paroxetine nor high-dose imipramine was apparently beneficial for major depression in adolescents, but there was an objective increase in harm with both drugs, and not with placebo. This shakes up the belief that published conclusions about the efficacy and safety of medicines are evidence-based and authoritative.
Reanalysis of Study 329 highlights the importance of transparent data to allow independent review of published results.
Implications for GPs
This is a wake-up call concerning the ethics and agenda of pharmaceutical research – and the possibly inherent bias of publications.
It also highlights the need for some caution in specific advice and recommendations that favour a specific approach and ignore others.
It brings us back to dialogue with specialist and non-specialist colleagues for shared decision-making for vulnerable patients.
This also reminds us of the need for individual counselling, information, treatment and follow-up, which may reveal that drug treatment is not always automatically the first answer, and that ‘First, do no harm’ remains a strong principle in modern medicine.
Early physiotherapy for low back pain2
Low back pain (LBP) is a common presentation in primary care, out-of-hours services or A&E.
There are some considerable international variations in management advice, with some guidelines specifically recommending delaying referrals for physical therapy.
This randomised trial in the US, with 220 adult patients (mean age 37.4 years) with recent onset of LBP (+/- radiation proximal to the knee), evaluated the efficiency of early physical therapy to improve disability. This was measured using the Oswestry Disability Index (ODI).
Four sessions of physical therapy were provided in the first four weeks after the initial assessment to half of the cohort.
Early physical therapy showed improvement relative to usual care in disability measured at four weeks and after three months – but not at one-year follow-up.
Perceived pain intensity was not measurably improved at four-week, three-month or one-year follow-up.
There were no differences in patients’ use of healthcare services at any point throughout the observation period.
Implications for GPs
The study authors’ conclusion, that early physical therapy resulted in ‘statistically significant improvement in disability’ but ‘without clinical importance’ compared with usual care, seems somewhat blunt or one-dimensional, and may have been influenced by the setup of a different healthcare system and other cultural factors.
It can be challenging to assess LBP objectively, and using scoring tools such as the ODI may be tempting. While they may be pragmatic, they may not compare well with individually examining and considering the short-term impact and consequences of acute LBP for the patient.
Health supplements and prostate cancer3
Men’s health supplements (MHSs) are increasingly being marketed to men for suggested health benefits, particularly ‘prostate health’. GPs may find themselves having to field questions from patients about these products.
This prospective study included 2,301 men, who were exclusively treated with intensity-modulated radiation therapy (IMRT) for prostate cancer (40% low-, 36% intermediate- and 24% high-risk) between 2001 and 2012.
About 10% of the patients reported taking MHSs (excluding general multivitamins, minerals and prescription medications).
The study evaluated overall patient outcomes with regard to the prostate cancer and toxicities from IMRT or MHSs.
The MHSs examined in this study contained a median of three identifiable ingredients, most commonly (91%) saw palmetto.
Other ingredients were no different to those found in standard multivitamins (5%), and 4% of the products did not seem to contain any identifiable ingredient.
MHS use could not be found to be associated with any apparent change of cancer-related outcomes or toxicities, in men who received IMRT for localised prostate cancer.
Implications for GPs
GPs in the UK probably rarely ask patients about taking any regular supplements, although the potential for interactions with prescribed medication could be considerable.
This study cannot objectively dismiss whether the MHSs under consideration may help in preventing (or slowing) the development or progression of prostate cancer in undiagnosed and asymptomatic men.
However, it highlights the need to be aware of the large commercially driven market of (possibly unproven) self-treatments, which may be medically useless or even potentially harmful.
Pharmacotherapy and prisoners with ADHD4
Long-term pharmacotherapy could cut the risk of imprisoned adults with ADHD reoffending, relapsing into substance abuse, or experiencing increased functional impairment, when compared with patients not taking medication.
In the study, 25 adult male prisoners with diagnosed ADHD in a Swedish high-security prison completed a five-week randomised, double-blind, placebo-controlled trial of methylphenidate, followed by a 47-week open-label extension of osmotic-release oral system methylphenidate.
They received follow-up at one and three years to assess ADHD symptoms (observed and self-reported), psychosocial functioning, substance misuse and criminal reoffending.
It is well established that imprisoned adult criminals have a high rate of ADHD. In this study, 75% of the treatment group were released from prison within the study period and 67% managed to secure full-time employment, with lower than expected negative impact of ADHD on their life.
The reported reoffending rate of 40% in this group was much lower than the expected >70% for this patient population with a previous conviction. The results suggest that continued medication, as well as motivational support, are important for improved long-term medical and social outcomes in adult offenders with ADHD.
The study authors pointed out that their observations needed validation from new and larger samples, but positive effects were maintained after four years of methylphenidate treatment. Most of those completing the study were employed and had no relapse in substance misuse or criminality.
Implications for GPs
Medical treatment of ADHD in adults is not well-established in the UK, owing to a lack of adequate specialist services for initiation and monitoring in many areas.
Although this study is not going to alter that situation, it focuses on the benefit of treatment in a high-risk group of ADHD patients and suggests considerable social and medical benefits in the long run, which may require and stimulate potential GP involvement.
Increased awareness of UK GPs regarding the potential diagnosis and management options for ADHD, particularly in criminal offenders, may help in reducing the burden of the condition for patients and society.
Coeliac disease and risk of developing dementia5
This study suggests, reassuringly, that ‘brain fog’, which can affect patients with coeliac disease, does not apparently increase the overall risk of developing dementia.
This population-based data review included 8,846 adults aged ≥50 years with histologically proven coeliac disease, and age- and gender-matched controls (n = 43,474). The overall median age of all participants was 63 years.
After a median follow-up of 8.4 years, 4.3% of the patients with coeliac disease and 4.4% of the controls were diagnosed with dementia. There appeared to be a minimally increased risk of vascular dementia in the first year after diagnosis, but this may be of little practical relevance.
Implications for GPs
Patients with coeliac disease are increasingly recognised as having a raised risk of other chronic conditions and are now more actively screened and informed about this.
Patients with coeliac disease frequently report cognitive symptoms or problems after exposure to gluten, which may cause concern. Some cognitive deficits have been found in patients newly diagnosed with coeliac disease.
The study concludes that there is no increased risk for dementia overall for patients with coeliac disease, which may help to reassure patients newly diagnosed with coeliac disease.
1. BMJ 2015; 351: h4320
2. JAMA 2015; 314(14): 1459-67
3. Int J Radiation Oncol 2015; 93: E194-5
4. J Clin Psychopharmacol 2015; 35(5): 535-43
5. J Alzheimers Dis 2015 Sep 29. Epub ahead of print. DOI: 10.3233/JAD-150388