Peripheral Neuropathy in Cancer and Fibromyalgia

Billions of dollars are spent annually worldwide on improving the prevention, detection and treatment of cancer. New drugs and treatment modalities are extending survival rates, with recent initial trials even inciting (probably prematurely) speculation of a cure.

Chemotherapy saves lives but it can also pack a big punch leaving survivors with an ME/CFS/FM-like condition

Despite impressive advances, though, cancer treatment remains aggressive with frequent debilitating side effects. These include the infamous ‘chemo-fatigue’ and ‘chemo-fog’, autonomic disturbances including orthostatic hypotension, and last but by no means least widespread pain due to treatment-induced peripheral neuropathy. Many of these side-effects, of course, are similar to symptoms commonly found in Fibromyalgia and Chronic Fatigue Syndrome.

Severe pain due to chemotherapy-induced peripheral neuropathy or CIPN (damage to peripheral sensory nerves) is often the limiting factor in the effectiveness and adherence to cancer treatments, as it limits the dose and duration of the cancer-killing drugs, and in extreme cases patients may choose to cease therapy – even when facing death.

With a series of recent studies finding evidence of small (and large) fiber neuropathy in at least 50% of fibromyalgia patients, the ‘central sensitization’ theory of FMS now looks to be incomplete.  In fact recent research into other neuropathic pain conditions suggests that ‘central sensitization’ requires ongoing peripheral nociceptive input.

While the exact mechanisms by which chemotherapy and related treatments cause peripheral neuropathy and neuropathic pain are still under investigation, there is little doubt that there is a causal relationship. With the culprits already known, chemotherapy agents can be readily tested in models of neuropathic pain.

Might research into the debilitating side effects of cancer treatment have the beneficial ‘side effect’ of improving the treatment of other ‘neuropathic pain’ conditions such as FMS and ME/CFS?

• When Cancer Treatment Packs a Painful Punch: Research into chemotherapy-induced neuropathy puts focus on mitochondria, but new therapies remain elusive by David C. Holzman on 6 Jun 2014 http://www.painresearchforum.org/news/41532-painful-chemotherapy-induced-neuropathy-tk

This excellent article, which has just been published on the equally excellent Pain Research Forum, reviews and summarizes recent findings on chemotherapy-induced peripheral neuropathy, the mechanisms involved, and current and future treatment options.

Rather than try to re-invent the wheel (and likely to fail in the process) I just want to highlight some of the key points and how they might relate to FMS and ME/CFS.

Key points

• CIPN is a common side effect of chemotherapy affecting between 20-70% of all patients and up to 100% with aggressive treatment. Curiously, not all patients receiving similar treatment regimes will develop neuropathy, and neuropathic pain may not appear for a few weeks to a few months after treatment commences – a phenomenon known as ‘coasting’ (more on this later).  Neuropathy may or may not resolve once treatment finishes.

• 

  A familiar cocktail of possible pathways to pain are found in post-cancer pain and ME/CFS and FM

  CIPN largely affects the sensory nerves with motor neurons usually spared. Damage to nerves in the autonomic nervous system can also occur.

• CIPN usually results in pain in the feet and hands that can be intermittent.  It may be stabbing, shooting, burning, tingling, or a combination of these.  It may cause numbness and cold or mechanical sensitivity.

• While the various chemotherapeutic drugs may result in CIPN through a variety of mechanisms or pathways, the resulting pathology is a familiar cocktail to ME/CFS and FM patients which involves pro-inflammatory cytokines, oxidative stress, mitochondrial damage/dysfunction, dorsal root ganglia, central sensitization, immune activation, and possibly microglial activation.

For example:

• In a rat model of CIPN induced by the chemotherapy agent paclitaxil, electron microscopy revealed that a proportion of the mitochondria in peripheral nerve tissue appeared to have ‘exploded’.  When the rats were left to recover their pain disappeared – as did the abnormal mitochondria. Paclitaxel (Taxol) caused mitochondrial energy production to drop drastically in neurons resulting in spontaneous (unstimulated) firing in 20-30% of sensory fibers, and further low doses of this or similar drugs worsened the pain.

• Mitochondrial dysfunction/nerve fiber damage leads to the formation of superoxide and other reactive oxygen species (ROS) that further impairs mitochondrial function and leads to more tissue damage.

• Other drugs may act more directly by entering the cell bodies and interfering with the DNA in the nuclei of sensory nerves in the sensory ganglia or via endothelial cell activation and immune cell infiltration into the nerve.

• 

  Some of the mitochondria in the nerve tissues of the post-cancer patients appeared to have ‘exploded’

  One researcher has presented a model of CIPN where the inflammatory cascade may start with the innate immune system.  The production of mitochondrial damaging ROS may be activated by the innate immune system’s detection of chemotherapy drugs by toll-like receptors (TLRs) that normally detect toxins from bacteria or viruses (PAMPS), tissue damage (DAMPS), or other ‘alarmins’ – the same pathway suspected of resulting in  activated microglia in the brain.

• This model may help explain the puzzle of why some patients remain pain-free and also the delay (coasting) in the onset of pain once chemotherapy starts.  Triggering of the innate immune system may start locally in response to damage to the dorsal root ganglia, but the inflammatory response draws in more immune macrophages in a growing ‘vicious cycle’ until the damage reaches a critical point where ‘sensations are altered and pain generated’.  It is suggested that, in some patients, this vicious cycle may ‘peter out’ before the critical point is reached.

• Data suggest that blocking TLR signalling blocks the production of ROS and the development of neuropathy.

Potential Treatments and Persons at Risk

“In the pipeline”

A cornucopia of drugs in development for preventing or reversing neuropathy, and for controlling pain, includes antioxidants, neuroprotectants, dietary interventions including fish oil and amino acid supplements, anticonvulsants, cannabinoids, opiates, and other analgesics, an antibiotic, cryotherapy, acupuncture, and more. 

Needless to say, neuropathic pain has been difficult to crack and despite numerous hypotheses, animal models, and promising results in vitro, few potential treatments have made the grade when subjected to clinical trials in humans. At present the only drug approved to treat CIPN pain is the antidepressant duloxetine (Cymbalta) which is moderately effective compared to placebo.

“But the degree of pain relief is not overwhelming”

The ultimate aim of being able to prevent or even reverse neuropathy is even more challenging.

An Intractable Problem?

Novel approaches to cancer pain relief could ultimately spell relief for FM and ME?CFS

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If this all sounds rather depressing, while CIPN remains a limiting factor in treatment outcomes in cancer, it’s a safe bet that pain research will continue to benefit from the considerable weight of cancer research funding. This can only be a good thing for chronically underfunded ‘Cinderella’ conditions such as FMS and ME/CFS where widespread potentially neuropathic pain is a common and debilitating symptom.

If research into such a complex and heterogeneous disease like cancer has progressed to the stage where ‘cures’ can be openly discussed, then chronic pain may not be such an intractable problem after all.  Pain researchers are now investigating novel pathways not targeted by traditional pain meds.

These include peroxynitrate (reactive nitrogen species cause similar damage to ROS), heat shock proteins (blocking the binding of HSP90 may also block chemo-induced nerve damage), minocycline (attenuates activated microglia), and adenosine receptor agonists (receptors involved in intracellular signalling which may be neuroprotective).

Early Detection

Another potential spinoff may be improvements in the early detection of peripheral neuropathy.  Research has shown that the presence of preexisitng subclinical (symptom-free) neuropathy in cancer patients predicts the occurrence and severity of peripheral neuropathy during chemotherapy.  It makes sense then to be able to identify these patients in advance and to tailor treatment to best minimize neuropathic pain.  The current test for neuropathy involves careful examination of a small skin-punch biopsy, but a new technique using microscopic imaging of nerve fibres in the eye might provide an objective test that is quicker and non-invasive.

Given the presence of common symptoms such as widespread pain and autonomic dysfunction, I, for one, would be interested to know if peripheral or autonomic neuropathy plays any role in ME/CFS, and a quick non-invasive test would make this a much more attractive research proposition.

For more details, the original (ten page) article is well worth reading.

The ME/CFS and FM Connection 

The finding that mitochondrial dysfunction resulted in spontaneous firing of the sensory neurons  – which was associated with increased pain -was novel and surprised the investigators, but mitochondrial dysfunction has been putatively associated with both fatigue and pain in ME/CFS and FM.

Novel pain relief agents in the drug pipeline could provide relief

Mitochondrial dysfunction has been found in the leukocytes and muscles of ME/CFS and FM patients respectively. A recent review of mitochondrial dysfunction in these disorders suggested a similar dysfunction in the central nervous system could lead to “generalized hypersensitivity and chronic widespread pain” – the same problem found in many post-cancer patients.

The author’s suggestion that oxidative stress could knock out the mitochondria in post-cancer pain patients was intriguing given repeated findings of increased oxidative stress in both FM and ME/CFS. Exercise has been shown to produce larger than normal amounts of oxidative stress which could possibly impact the mitochondria.  ( High initial oxidative stress levels improved with exercise in FM, however. )

Coenzyme Q10 (a vital factor in ATP production) and ATP production were significantly reduced in the PBMC’s of ME/CFS and FM patients while lipid peroxidation in the ME/CFS patients was significantly increased. COQ10 depletion may, in fact, be a common finding in neuropsychiatric disorders associated with fatigue and altered mood.

However it occurs, whether through chemoptherapy agents or infection or through some other process the latest work in post-cancer pain suggests similar pathways could be producing pain, fatigue and cognitive problems in all three disorders. If that’s true then work on post-cancer pain could be a boon to all of us.

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