Nortriptyline and duloxetine are the best, but not great options for managing patients with cryptogenic sensory polyneuropathy (CSPN).

A US study of 402 patients from 40 clinical sites comparing nortriptyline, duloxetine, pregabalin and mexiletine found there was a need for new, more effective drugs for idiopathic neuropathic pain.

The PAIN-CONTRoLS study, published in JAMA Neurology, used a combination of efficacy and drop-out rates at 12 weeks to create a single outcome measure and compare the utility of the four drugs.

It found medication quit rates – for any reason but usually adverse events – were lowest in nortriptyline (38.1%) and duloxetine (37.3%) compared to pregabalin (42,5%) and mexiletine (58.0%).

Efficacy, defined as at least a 50% reduction in pain, was low with all drugs but marginally higher in nortriptyline (25.4%) and duloxetine (23.0%) compared to pregabalin (15.1%) and mexiletine (20.3%).

Combining the outcomes into a utility function score showed nortriptyline (0.81) and duloxetine (0.80) were superior to either pregabalin (0.69) or mexiletine (0.58).

“The probability that the treatment has the best utility was 0.52 for nortriptyline, 0.43 for duloxetine, 0.05 for pregabalin, and 0.00 for mexiletine,” the study said.

It said the findings support duloxetine and nortriptyline as the better-performing drug choices in this patient population with neuropathic pain.

“However, this study also supports a finding that all 4 drugs helped improve pain in at least some patients, so each could be tried if others failed.”

Commenting on the study Dr Neil Simon, from Northern Beaches Neurology and head of neurology at the Northern Beaches Hospital in Sydney, told the limbic the findings were somewhat depressing.

“Nortriptyline, which is something I use occasionally, was only effective in 25% of people. The thing is that the placebo effect can be up around 25-30%. I’m not saying the placebo effect is there but …it’s a very modest rate of improvement and then the other thing is that 38% [of patients] didn’t continue because of the side effects. And that was the best performing medication.”

“It’s a really interesting paper because it shows how bleak the treatment options are and maybe, in the light of these figures, we should be reconsidering how we use some of these medications.”

He said a multimodal approach was needed.

“There are a bunch of options. For example, there are a few things that I will talk to patients about outside of pills in a packet. There are non-medication options like physical activity, lifestyle changes and devices.”

“It depends partly on the distribution and nature of their symptoms but let’s just say its feet and legs. There are some devices which provide mechanical and electrical stimulation. It’s not heavily data driven, it’s more empiric, but that is certainly something I would recommend particularly for patients who have milder symptoms, or who have a lot of other medications, or in the elderly where adding in one of these fairly toxic medications, could cause issues.”

He said some patients also appeared to benefit from alternative approaches such as α-lipoic acid and palmitoylethanolamide (PEA).

“And again there is no strong data but …generally speaking they have minimal side effects and you can gain a response in some patients without much hazard associated with it.”

“Pain is not only an electrical or a chemical phenomenon. Pain is a psychological, physical, chemical and electrical phenomenon and you can address all those. If we only focus on drugs that affect the gabaminergic circuits which have been shown to have a role in pain, that’s missing out on a lot of different elements of pain management.”