Neuropathic pain - caused by damage to nerve cells - is well-known to be tough nut for pharmaceutical developers to crack, and the mainstays of treatment remain elderly drugs including tricyclic antidepressants, epilepsy drugs and anaesthetics.
For some patients opioid painkillers are the only effective remedy, but these should be used sparingly to reduce the risk of side effects and addiction.
Now, researchers in Canada have shown that the task of developing new therapies is being made even more challenging by the placebo effect, which seems to have become more pronounced in trials in recent years.
The team from McGill University analysed the results of trials conducted between 1990 and 2013, revealing that the pain inhibition experienced by patients in the placebo group increased steadily, reaching an average 30% decrease in pain levels among trials published in the final year of dataset.
Put another way, that means patients in 1996 said that on average drugs were 27% more effective at alleviating pain than placebo, but in 2013 the difference had slipped to 9%.
Rising placebo responses make it harder to differentiate between the active treatment and control groups, raising the efficacy bar for new drug candidates, and could explain why so many drugs for neuropathic pain have failed in late-stage testing over the last decade.
Similar increases in placebo response have previously been observed in studies of clinical trials of antidepressants and antipsychotic drugs, according to the researchers, led by McGill's professor of pain studies Jeffrey Mogil.
US Effect and rising use of CROs
Bizarrely however, the rising placebo responses only seemed to affect studies carried out in the US - trials in Europe and other parts of the world seemed to be unaffected by the phenomenon.
The authors suggest this may result in part from direct-to-consumer (DTC) advertising in the US which could have increased the public's expectations for the beneficial effects of drugs.
The rising use of contract research organisations (CROs) could also be playing a part however - they suggest that CRO-led trials may introduce a higher level of patient contact and care than generally occurs with academic investigators, and this could affect the outcome.
The researchers also found that trials seem to be getting longer. It is feasible that this could be a consequence of the higher efficacy hurdle - which in turn will hike costs for sponsors - but Mogil has suggested the increased dollars spent on studies could also be transmitting a feel-good factor to subjects.
It is estimated that 7%-8% of the adult population suffer from chronic pain linked to neuropathy - often as a consequence of diabetes, shingles and surgery, Around 40% of cases do not respond to current first-line treatments and 25% are resistant to second-line therapies.
Given the lack of effective medicines for neuropathic pain and the size of the population, drugmakers continue to invest heavily in candidate therapies.
In June, Novartis bought Australian pharma developer Spinifex for $200m upfront in order to get access to its EMA401 candidate for shingles-associated pain, while in January Biogen announced a deal valued at up to $675m to acquire the UK's Convergence and its pipeline of neuropathic pain drugs.
The placebo study has been published as an early-access paper in the journal Pain, the journal of the International Association for the Study of Pain (IASP).