In April 2019, we published a study (in the link below) called “Somatosensory Predictors of Response to Pregabalin in Painful Chemotherapy Induced Peripheral Neuropathy: a Randomized, Placebo-Controlled, Crossover Study”.
I’ll try to explain in simple terms 1) why did we decide to do the study, 2) how did we do it, 3) what did we find, and 4) what does it mean.
1. So why did we do the study?
Chemotherapy-induced peripheral neuropathy (abbreviated as CIPN) is a very bothersome complication of certain types of anti-cancer drugs. As if it’s not bad enough that a person has a diagnosis of colon or breast cancer and may needs to undergo surgery, radiation therapy, and many cycles of chemotherapy that cause nausea, vomiting, hair loss, and a lot of other nasty side effects – a substantial amount of patients receiving chemotherapy (for example, drugs called oxaliplatin or paclitaxel) develop this condition called CIPN. CIPN is characterized by pain, tingling, burning, and numbness – mostly in the feet, and sometimes in the hands. The good news is that in many patients the symptoms lessen over time and sometimes disappear almost completely. The bad news is that even a year after completing chemotherapy, about 20% of patients treated with these particular drugs suffer from symptoms of CIPN, which really disturbs their quality of life.
So you might ask: There are a ton of analgesics available – why not just treat these patients’ pain?
That’s a good question. The problem is that CIPN is quite a resistant condition, and typically analgesics like acetaminophen (paracetamol), non-steroidal anti-inflammatory drugs (like ibuprofen), and even opioid medications don’t really help. Even medications such as gabapentin or amitriptyline, which are specifically used for other types of painful neuropathy, seem to be really helpful only on rare occasion in patients with CIPN.
But, then, how do we help patients with CIPN?
In an attempt to understand why these types of chemotherapy cause neuropathy, and to identify molecules and receptors that could be useful targets for treating CIPN in humans, researchers have developed models of CIPN in animals. Briefly, if you repeatedly inject these types of chemotherapy into mice or rats, they develop hypersensitivity in their paws – i.e. if you poke their paws with a thin nylon filament or with something cold (that usually is not too unpleasant to a healthy mouse or a rat), the rodents now don’t like that and move their paw away from that “stimulus”. Since we cannot ask the rodents how much pain they have, this “hypersensitivity” behavior is typically interpreted as a sign of neuropathy.
Many patients with neuropathy also develop overt sensitivity to crude or light touch, or to temperatures that are too cold or too hot, so that it’s not too far-fetched to think that this hypersensitivity in rodents is somewhat similar to painful neuropathy in humans. There are drugs, that when given to these mice and rats (including drugs like pregabalin, that are clinically useful for treating various painful neuropathies), reduce that hypersensitivity to mechanical poking.
But here is the challenge — not all patients who develop CIPN present with this sort of increased sensitivity in their feet and hands. In fact, many patients report that they have a loss of sensation. Their feet are numb and yet they feel like burning, tingling, and they hurt all day, every day.
There are several complex issues related to translating animal findings to humans (even just because mice are not just small fuzzy people, as my colleague Rob Gereau says), and I cannot address many of these here. But this study is about simply one of these points:
Let’s assume this increased sensitivity in mice and rats is indeed representative of painful neuropathy in humans. For some reason, however, all mice and rats develop hyper-sensitivity to mechanical stimulation after receiving chemotherapy, but it occurs only in a fraction of patients. Therefore, the starting point for this research was something like this: “maybe drugs like pregabalin work only for humans who develop hypersensitivity to mechanical poking, as a part of their CIPN symptom profile, and they don’t work as well in patients who have sensory loss.”
2) How did we do the study?
To test our assumption, we used a measure of mechanical hypersensitivity called Mechanical Pain Threshold. We apply thin weighted metal probes to the painful area on the patient’s feet, to determine the intensity of a mechanical stimulus that causes a sharp or painful sensation.
So with the help of a fantastic collaborative team, we identified patients who developed CIPN following their chemotherapy, and who kindly agreed to participate in the study.
The participants completed a battery of various tests and questionnaires at baseline, and were then randomized to receive a 4-week treatment with a drug called pregabalin (Lyrica), followed by 4 weeks of placebo (identically looking pills that do not have an active drug in them), or in reversed order. Randomization means that the sequence of their treatments was determined randomly, like by flipping a coin. The participants were asked to rate their pain (daily, on a tablet device) on a 0-10 scale, where 0 is no pain, and 10 is the worst imaginable pain.
Performing a clinical study is quite an expensive endeavor. We submitted a research proposal to the ASPIRE investigator-initiated grant program run by Pfizer Inc (the manufacturer of pregabalin), and received a research grant (as well as the study drug) to help perform the study.
3) What did we find?
Overall, 26 patients met all the inclusion criteria and participated in the study. 23 of these patients received both pregabalin and placebo treatments.
We found that overall, the extent of mechanical sensitivity (or mechanical pain threshold) was not predictive of how much pain relief (on a 0-10 scale) the patients received with the drug or with the placebo pill. In addition, although pregabalin seemed to somewhat relieve the pain over the 4-week treatment period, overall it did not significantly outperform the placebo in this particular condition.
Interestingly, when we looked at particular symptoms such as pain evoked by touch, or sensations like pressing pain or unpleasant tingling, pregabalin alleviated these symptoms better than the placebo.
4) What does it mean?
There are a few take-home messages from this study.
First, when measured on a 0-10 scale, pain from CIPN does not seem to be relieved substantially with pregabalin, compared to placebo.
Second, our assumption that “if pregabalin works in mice and rats with chemotherapy-induced mechanical hypersensitivity, it may also work in humans with chemotherapy-induced mechanical hypersensitivity” was not confirmed.
An important thing to understand in this context is that all rodents, as well as a subset of our human patients, develop the “profile” of mechanical hypersensitivity as a part of their CIPN. However, in mice and rats, that mechanical hypersensitivity is also the measure of drug effectiveness – i.e. we are looking if the hypersensitivity diminishes following treatment. In humans, on the other hand, the measure of effectiveness was the rating of their pain on a 0-10 scale, which is quite different from the sensitivity to mechanical probes applied to the skin.
In this context, it is maybe naïve to assume that what people think about when they rate their pain is the direct amount of tingling or burning sensation in their feet, or the unpleasantness of a mechanical object touching their feet. It is more likely that what goes into that “pain number” is something much more complex – for example the inability to sit through a family dinner without needing to lay down after 30 minutes because of the unbearable pain, or maybe the constant anxiety or fear that “this pain is never going to go away” that paralyzes them and ruins their quality of life. And animal models likely fail to capture that element related to human suffering.
As such, it was interesting to see that those particular measures such as tingling, pressing sensations, and pain evoked by touch did improve with pregabalin, just as they improved in mice and rats – and maybe this is just the first step in this “animal-to-human” translation. We should work further to both improve the animal models to understand the “suffering” component of the pain, and not merely the hypersensitivity, but also refine our clinical measures in humans to find out how changing some of the “sensory” parameters can reduce true human suffering due to painful neuropathy.
On behalf of the research team, I would like to sincerely thank all the patients who volunteered to participate in this study. We could not have done it without you!