Bad medicine: the rise of duloxetine

Des Spence’s polemic about duloxetine [1] loses most of its power because almost every assertion he makes is wrong. Using references to support a point of view doesn’t help much when they out-of-date and superseded by new knowledge or more relevant evidence. We assume that it is not ignorance of the arguments but a deliberate attempt to provoke, despite the reasoned arguments of science. It succeeded in this because the management of chronic pain is important irrespective of what the pharma industry says.

The research is dense and complex, but we know an increasing amount about the bio-psycho-social origins of pain. Research in genetics, neurobiology, and imaging have established how astonishingly complex acute and chronic pain can be; the brains of people with chronic pain are very different from those of us lucky enough not to have it.

Without wanting to be comprehensive, here is a brief list of where Spence misses the point:

Medicalising of chronic pain. This calumny on patients has been dismissed before [2]. The definition of chronic pain is having pain of moderate or severe intensity for three months or more (think of a really bad headache lasting from Christmas to Easter). It affects 1 adult in 5 [3]; painful conditions are not only amongst the most prevalent of common conditions, but represent 5 of the top 11 conditions in terms of years living with disability [4]. Chronic pain destroys lives, has a huge negative impact on quality of life [5], is costly, reduces the ability to work or function inside the family [6], and may be associated with decreased life expectancy [7].

Women are over-represented. Chronic pain disproportionately affects women. Their representation inside clinical trials pretty well matches the epidemiology.

Soft rating scores. Yes, patients report their pain themselves: there is no other way of doing it, and it is their experience, after all. Pain is the most immediate of the patient outcome measures. High quality clinical trials in pain began in the 1950s, and the subjectivity of pain was recognised from the beginning. Pain scoring shows excellent agreement between different scales (pain intensity, pain relief, for example). Patients in clinical trials record consistent pain levels over long periods, much as in clinical practice.

Actual benefits … over placebo are of the order of 1 point on a 10 point rating score. Yes they are, if you take the average. But few patients are average, most having either very little or a great deal of benefit. The most recent standard is for a responder, defined as a patient having at least 50% pain intensity reduction maintained for 12 weeks, and without intolerable adverse events that mean stopping treatment [8]. This is the outcome that patients themselves want and it is accompanied by improvements in sleep, function and quality of life [9].

Other Cochrane reviews find effective non-drug alternatives: No they don’t. The effects of exercise on pain in fibromyalgia involved only 223 patients in four small trials of barely adequate quality [10]. The most recent Cochrane review of psychological therapies is uncompromising that any effects are at best weak, with an urgent need of improved research [11].

Duloxetine prescribing is endorsed by a Cochrane review. The review [12] ‘endorses’ nothing. It simply says that there is good evidence from a number of good quality trials that duloxetine is effective in painful diabetic neuropathy and fibromyalgia. It then says there is no evidence within the context of the title to support any other use. The effect size is not massive; an NNT of 5 tells you that, but it is comparable to other treatments in neuropathic and other chronic pain where treatment failure is to be expected more often than treatment success [13, 14].

Predictably, the expert academic guardians are steeped in conflicts of interest. Yes, some (but by no means all) made declarations of interest, not quite the same as conflicts. And proud of being able to, when it means bringing otherwise unpublished information into the public domain, accessing data at the level of the individual patient to improve understanding of evidence and outcomes, or demonstrating new sources of large potential bias. We have had a rule in being for over 30 years, that we only work with commercial or other concerns as long as there is an unrestricted right to publish the results, whatever the results may be.

Spence omits important criticisms. For example, there is the bias against older therapies because authorities require trials fundable only by industry or government. Effective drugs like amitriptyline are under-studied and consequently have less evidence of efficacy to support their use. And the fact that inappropriate imputation methods in statistical analysis of results can mean that efficacy can sometimes be inflated hugely [15]. That is not the case for duloxetine [16].

Now, we enjoy polemic as much as the next 'pointy-headed' academic, and we are not averse ourselves to prodding the pompous and powerful. But we passionately believe that people suffering in pain deserve better than Des’ output. Making self-appointed pronouncements in highly respected journals about what is good and bad medicine comes with a responsibility to know what you are talking about. Bad scholarship helps no-one, especially those in pain.

So, come on Des. Keep up!

From

Andrew Moore, Phil Wiffen: Pain Research and Nuffield Division of Anaesthetics, Nuffield Department of Clinical Neurosciences, University of Oxford, The Churchill, Oxford OX3 7LE
Christopher Eccleston: Centre for Pain Research, The University of Bath, Bath BA2 7AY, UK
Micael Lunn: National Hospital for Neurology and Neurosurgery, Department of Neurology and MRC Centre for Neuromuscular Diseases, London, UK
Richard Hughes: National Hospital for Neurology and Neurosurgery, MRC Centre for Neuromuscular Diseases, London, UK
Amanda Williams: University College London, Research Department of Clinical, Educational & Health Psychology, London, UK
Dominic Aldington: Consultant in Pain Management, Royal Hampshire County Hospital, Winchester, Hants, UK
Eija Kalso: Institute of Clinical Medicine, Faculty of Medicine, University of Helsinki and Pain Clinic, Department of Anaesthesia and Intensive Care Medicine, Helsinki University Central Hospital, P.O. Box 140, FIN-00029 HUS, Finland

References:

1. Spence D. Bad medicine: the rise of duloxetine. BMJ 2014;348:g139
2. Williams AC, Johnson M. Persistent pain: not a medically unexplained symptom. Br J Gen Pract 2011;61:638-9
3. Breivik H, Collett B, Ventafridda V, Cohen R, Gallacher D. Survey of chronic pain in Europe: prevalence, impact on daily life, and treatment. Eur J Pain 2006;10:287-333
4. Vos T, Flaxman AD, Naghavi M, Lozano R, Michaud C, Ezzati M, et al. Years lived with disability (YLDs) for 1160 sequelae of 289 diseases and injuries 1990-2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 2012;380:2163-96
5. Sprangers MA, de Regt EB, Andries F, van Agt HM, Bijl RV, de Boer JB, et al. Which chronic conditions are associated with better or poorer quality of life? J Clin Epidemiol 2000;53:895-907
6. Moore RA, Derry S, Taylor RS, Straube S, Phillips CJ. The costs and consequences of adequately managed chronic non-cancer pain and chronic neuropathic pain. Pain Pract 2014;14(1):79-94
7. Torrance N, Elliott AM, Lee AJ, Smith BH. Severe chronic pain is associated with increased 10 year mortality. A cohort record linkage study. Eur J Pain 2010;14:380-6
8. Moore RA, Eccleston C, Derry S, Wiffen P, Bell RF, Straube S, et al; ACTINPAIN Writing Group of the IASP Special Interest Group on Systematic Reviews in Pain Relief; Cochrane Pain, Palliative and Supportive Care Systematic Review Group Editors. "Evidence" in chronic pain – establishing best practice in the reporting of systematic reviews. Pain 2010;150:386-9
9. Moore RA, Straube S, Aldington D. Pain measures and cut-offs – 'no worse than mild pain' as a simple, universal outcome. Anaesthesia 2013;68:400-12
10. Busch AJ, Barber KA, Overend TJ, Peloso PM, Schachter CL. Exercise for treating fibromyalgia syndrome. Cochrane Database Syst Rev 2007;4:CD003786
11. Williams AC, Eccleston C, Morley S. Psychological therapies for the management of chronic pain (excluding headache) in adults. Cochrane Database Syst Rev 2012;11:CD007407
12. Lunn MP, Hughes RA, Wiffen PJ. Duloxetine for treating painful neuropathy, chronic pain or fibromyalgia. Cochrane Database Syst Rev 2014;1:CD007115
13. Kalso E, Aldington DJ, Moore RA. Drugs for neuropathic pain. BMJ 2013;347:f7339
14. Moore A, Derry S, Eccleston C, Kalso E. Expect analgesic failure; pursue analgesic success. BMJ 2013;346:f2690
15. Moore RA, Straube S, Eccleston C, Derry S, Aldington D, Wiffen P, et al. Estimate at your peril: imputation methods for patient withdrawal can bias efficacy outcomes in chronic pain trials using responder analyses. Pain 2012;153:265-8
16. Moore RA, Cai N, Skljarevski V, Tölle TR. Duloxetine use in chronic painful conditions ¬– individual patient data responder analysis. Eur J Pain 2014;18:67-75