Something potentially amazing just happened. I’m not being flippant, a randomised controlled trial (RCT: still the only research method that can genuinely tell whether a treatment works) from China has just produced results in chronic back pain that can only be described as amazing. The temptation is to say “unbelievable”. This trial published in the worlds premier pain journal might have completely passed me by had it not been accompanied by an editorial with the headline “A cure for back pain?” written by Professor Nikolai Bogduk. If you think that headline is an attention grabber (although note the question mark), the results of the trial are even more so.
The trial compared injecting a substance called methylene-blue (which is known to kill nerve fibres) into the discs of chronic back pain sufferers with placebo injections. The idea is that in chronic back pain the degeneration that affects the intervertebral discs causes increased nerve growth and this sensitizes the disc. The brain produces pain in response to the increase in noxious input. Patients were selected if they had “discogenic” chronic back pain (i.e. back pain caused by a sick disc). This was established using discography, a diagnostic test during which the discs are injected to provoke pain. If this provokes the patients back pain symptoms then the test is considered positive.
The results of the trial are show-stoppers. 73% improvement in pain and disability for the real therapy versus 1% and 3% improvement respectively in the placebo group. 91% patient satisfaction with the real treatment versus 14% for placebo. To give you an idea of scale there are no therapies out there for chronic back pain that one could honestly describe as being more than moderately or marginally effective for chronic back pain, in fact nearly all of our therapies dance around the threshold of what we might consider minimal clinical significance (often defined as around 15% improvement) (for example see here and here). It is important to note that nobody is suggesting that here is a treatment for all chronic back pain. This trial suggests that there is a subgroup of people with “discogenic” chronic back pain, that can be identified by discography and that these patients are likely to be helped by this treatment.
So then, job done, disc-related back pain cured? Happy Days?
There may be reasons to be cautious and interestingly they are not in the trial methodology itself. These results literally blow everything else out of the water – and that is the problem. Prof Bogduk points out that the trial appears well designed and without fatal flaws and yet the results are unprecedented. He wonders whether cultural factors may have influenced patient reporting, but if blinding of the patients and the researchers was maintained then this shouldn’t be an issue. The point he makes is that when results are so incongruous with the existing evidence base final judgement should be reserved until they pass the ultimate scientific hurdle: replication by independent groups in different patient populations.
There are other reasons why the results are so surprising. The evidence regarding the accuracy of discography as a diagnostic test is conflicting (see here and here). Of course an inaccurate diagnostic test should be expected to disadvantage a therapy in a trial, not inflate the benefits as you would recruit more inappropriate patients. There are other existing treatments that also aim to destroy the nerve supply of the disc (such as radiofrequency or thermal denervation). As the authors of the trial acknowledge these treatments have not performed well in RCTs to date, so what is different about methylene blue? Another possible cause for concern is that lack of any meaningful response in the group that received placebo injections. This lack of response may be due to the fact that the earliest point that patients were followed up was 6 months after the treatment and we know that even in the short term the placebo effect in clinical trials is quite unstable. In other trials of similar disc treatments we see the same pattern. One trial demonstrated a 17% improvement in pain scores at 6 months with placebo treatment (versus 37% with the real treatment) whilst another trial found essentially no change at all in either group. Nonetheless the lack of any placebo response to such an elaborate and invasive procedure is curious.
The patients recruited in this trial would fall under the diagnostic umbrella of “non-specific low back pain” (which really means “we don’t know the cause”). This umbrella accounts for about 85% of all back pain cases. When we look at the factors that influence the prognosis of this type of back pain we find little of use. There really is no measure of spinal pathology that is predictive of outcome (including discography and modern imaging technology), in fact commonly the only factors that seem to influence outcome are the severity of the patients pain and a number of psychosocial variables. This had led many to move away from a model of chronic back pain that has spinal damage at its core and to the development of biopsychosocial models that recognise that the pain and disability may be influenced by non-spinal factors. Indeed in response to evidence of abnormal pain processing in chronic pain patients some have speculated that chronic back pain is a problem of central nervous system pain processing (also see here and here). If the results of this trial accurately reflect the efficacy of methylene blue then this model will have taken a significant knock and as scientists we may need to reappraise.
Finally there is a phenomenon in research known as small study effects. Often early small studies exaggerate the effect size of treatments and the ensuing large studies produce more conservative results. This study is neither very small nor impressively large but the methods appear sound. It is simply unfair to dismiss these findings and to be clear none of the above discussion aims to do that. But when research findings are so at odds with the existing body of evidence it is fundamental to scientific enquiry to consider them as interesting and encouraging but then to wait and see what follows. I think a follow up blog in 3 to 5 years time would be a good idea and I am not yet ready to send my chronic back pain patients for a shot of blue, nor to encourage them to see disc degeneration as the fundamental cause of their problem. But that could change…..
Original Article Abstract
Peng B, Pang X, Wu Y, Zhao C, & Song X (2010). A randomized placebo-controlled trial of intradiscal methylene blue injection for the treatment of chronic discogenic low back pain. Pain, 149 (1), 124-9 PMID: 20167430
A preliminary report of clinical study revealed that chronic discogenic low back pain could be treated by intradiscal methylene blue (MB) injection. We investigated the effect of intradiscal MB injection for the treatment of chronic discogenic low back pain in a randomized placebo-controlled trial. We recruited 136 patients who were found potentially eligible after clinical examination and 72 became eligible after discography……
For full abstract and article go here
Editorial
Bogduk N (2010). A cure for back pain? Pain, 149 (1), 7-8 PMID: 20129734