Today's post from prohealth.com (see link below) asks the question whether both small fibre and large fibre neuropathy are present in Fibromyalgia. Fibromyalgia is a disorder characterized by widespread musculoskeletal pain accompanied by fatigue, sleep, memory and mood issues and many patients have also reported the sort of widespread neuropathic symptoms readers of this blog are familiar with. However, experts have long tried to keep the two conditions apart, having found no proof that they can be concurrent. Then it was concluded that small fibre neuropathy may well be a symptom of fibromyalgia and now, they've added large fibre neuropathy to the mix as well. The consistent aching associated with fibromyalgia is thought to be caused by the way the brain handles pain but that is very close to the root cause of neuropathic symptoms too. Fibromyalgia patients also typically suffer symptoms above the waist and neuropathy sufferers below the waist but when the patient has both sets of symptoms, the root cause must be pretty much the same and the consequences for the patient are miserable to say the least. At least they are now thinking that both conditions are neurological and therefore symptomatic of nerve damage somewhere in the nervous system. Equally importantly it has now been found that both show demyelinating damage (damage to the protective lining of the nerves) leading to undeniable connections between both diseases.
By Cort Johnson • www.ProHealth.com • June 11, 2014
Reprinted with the kind permission of Cort Johnson and Health Rising.
We report here a surprisingly high prevalence of clinical and electrodiagnostic (EDX) abnormalities implying a demyelinating polyneuropathy, suggestive of chronic inflammatory demyelinating polyneuropathy (CIDP), in FMS. Caro et. al 2008
With three studies finding evidence of small fiber neuropathy in significant numbers of people with Fibromyalgia, the skin has become of increasing interest. (Small fiber neuropathy refers to damage to the small nerve fibers in the skin. Skin biopsies are used to determine if SFN is present).
Caro was the latest researcher to find evidence of nerve problems in FM and it turns out, he was the first as well.
From Immune Problems in the Skin
Science often moves slowly and it has in this case as well. Thirty years ago in 1984 Caro found evidence of an autoimmune process – IgG antibodies in the dermal-epidermal junction – in the skin of people with FM. Two years later he validated his findings in a blinded study. That same year Dineman found increased prevalence of Raynaud’s phenomenom, dry mouth, low complement, ANA and IgG antibodies in the skin as well. Something unusual appeared to be occurring in the skin of people with FM but progress defining it was slow.
To the Nerves….
In 1988, Sim’s study “Symptoms mimicking neurological disorders in Fibromyalgia” put a focus on the nerves. Caro reported on nerve conduction tests in FM in 2005 and then in 2008 provided the first evidence of peripheral neuropathy.
Small fiber neuropathy is kind of the rage in FM right now, but Caro’s 2008 study suggested that larger nerve neuropathy (demyelination) was also present. In this article, we take a look at that 2008 study containing 58 Fibromyalgia patients.
The Study
X. J. Caro, E. F. Winter and A. J. Dumas. A subset of fibromyalgia patients have findings suggestive of chronic inflammatory demyelinating polyneuropathy and appear to respond to IVIg. Rheumatology 2008; 47;208–211
A ‘demyelinating polyneuropathy’ was reported present when EMG and nerve conduction studies revealed nerve conduction speeds two (and often three) standard deviations below normal in two or more nerves. (Nerve signals travel more slowly in demyelinated nerves.). Caro, et. al followed standards proposed by the Inflammatory Neuropathy Cause and Treatment (INCAT) group for demyelinating polyneuropathy.
The Findings
With 76% of patients reporting paresthesias (tingling), 88% percent reporting hypaesthesia (loss of sensation – with increased loss in the lower extremities) and 90% reporting weakness, the symptom presentation in FM suggested nerve damage was present. (The ‘stocking distribution’ of nerve symptoms which involves worsening symptoms the further down the limbs one goes is highly emblematic of peripheral nerve disorders.)
Greatly increased rates of nerve symptoms as well as muscle weakness in people with FM (90%) compared to people with rheumatoid arthritis (13%) suggested FM was a far different type of disease than it’s rheumatological counterpart. (Martinez-Lavin found that 95% of FM patients as opposed to 30% of RA patients reported sensory symptoms as well).
Nerve conduction studies revealed a polyneuropathy was present in almost 50% of their FM patients. Seventy percent of the FM patients with polyneuropathy had evidence of demyelination. (Note that demyelination refers to large nerve fibers; small nerve fibers are not myelinated.) Sural nerve biopsies suggested myelin injury (segmental de and re-myelination and/or myelinated nerve fiber dropout) had occurred in the majority of those tested. (They revealed no vasculitis or amyloidosis and provided little evidence of what was causing the demyelination.)
Chronic Inflammatory Demyelinating Polyneuropathy
Comparing FM to chronic inflammatory demyelinating polyneuropathy (CIDP), Caro put FM squarely in the realm of an immune mediated neurological disorder.
CIDP is an inflammatory disorder affecting the peripheral (as opposed to the central) nervous system. Considered a chronic form of Guillain-Barre disease, CIDP is characterized by the loss of the myelin sheath in the larger nerves in the body.
The symptom presentation is quite heterogeneous and includes weakness, fatigue, numbness, tingling, pain, difficulty in walking, burning pain in the extremities, and sudden onset back or neck pain radiating down to the arms and /or legs. Loss of deep tendon reflexes (rarely increased or normal), loss of muscle mass and fasciculations (twitching) may be present. Autonomic dysfunction can cause problems standing (orthostatic intolerance, bladder, bowel and/or cardiac problems).
Left untreated about 30% of CIPD patients will end up in a wheelchair.
FM patients were determined to have a CIDP-like illness when they exhibited lower extremity stocking hypaesthesia (loss of sensation), muscle weakness in at least two extremities, and evidence of a demyelinating polyneuropathy.
Following Latov’s proposal that “most acquired demyelinating neuropathies of otherwise unknown etiology are considered to be a form of CIDP’, Caro and Winter proposed that a significant subset of FM patients have a form of CIDP.
CIDP is another disorder with decided overlaps with ME/CFS and FM. As with ME/CFS, the lack of agreed upon clinical criteria have thwarted clinical trials. It’s widely acknowledged that the criteria often used to diagnose CIDP misses many leaving many untreated (including ME/CFS and FM patients????)
Treatment
Treatments include steroids, IVIG and immunosuppressive drugs such as Rituximab. Suspecting that an immune mediated nervous system disorder similar to CIPD was present Caro started IVIG treatment in 15 patients. A ‘large percentage’ reported significant improvements in pain, tender points and strength.
Update
Since Caro’s 2008 report indicating reduced nerve conduction and possibly demyelination of the large nerves in the body, Nacir, et. al found widespread evidence of decreased nerve conduction velocity in the upper bodies of FM patients.
Conclusion
This study and others suggest that some people with FM could have both small and large fiber neuropathies. If you have symptoms similar to those described above, nerve conduction tests (for the large fiber neuropathy) and skin biopsies (for the small) may be warranted.
Caro and others propose that the neuropathies in Fibromyalgia are probably immune mediated and propose immune therapies for them.
About the Author: Cort Johnson has had ME/CFS for over 30 years. The founder of Phoenix Rising and Health Rising, Cort has contributed hundreds of blogs on chronic fatigue syndrome, fibromyalgia and their allied disorders over the past 10 years. Find more of Cort's and other bloggers' work at Health Rising.
http://www.prohealth.com/library/showarticle.cfm?libid=18996
Today's post from cochrane.org (see link below) follows on from yesterday's post, in that it looks at studies and clinical trials of the effectiveness of morphine on neuropathic pain. It's conclusions, that there is little evidence that morphine helps with neuropathic pain, are (as they themselves point out) a little misleading because the studies it examines, are just too small to reflect accurate results. The whole point of the article is to call for much larger studies on the effectiveness of morphine and other opioids on nerve pain. Why there seems to be a reluctance to carry out these studies is mystifying in the current climate of hostility towards opioids but one thing is sure: large scale examination of the true effect of these drugs is not only essential...it's urgent! 
Published: 22 May 2017 Authors: Cooper TE, Chen J, Wiffen PJ, Derry S, Carr DB, Aldington D, Cole P, Moore R Primary Review Group: Pain, Palliative and Supportive Care Group
Bottom line
There is very low quality evidence that morphine taken by mouth has any important effect on pain in people with moderate or severe neuropathic pain.
Background
Neuropathic pain comes from damaged nerves. It is different from pain messages that are carried along healthy nerves from damaged tissue (a fall or cut, or arthritic knee). Neuropathic pain is often treated by different medicines (drugs) to those used for pain from damaged tissue, which we often think of as painkillers. Medicines that are sometimes used to treat depression or epilepsy can be effective in some people with neuropathic pain. Opioid painkillers are sometimes used to treat neuropathic pain.
Opioid painkillers are drugs like morphine. Morphine is derived from plants or synthesised by chemists. Morphine is widely available for use as a painkiller, usually given by mouth.
Our definition of a good result was someone with a high level of pain relief and able to keep taking the medicine without side effects making them want to stop.
Study characteristics
In February 2017, we searched for clinical trials in which morphine was used to treat neuropathic pain in adults. Five studies satisfied the inclusion criteria, randomising 236 participants to treatment with morphine, placebo, or other drugs. Studies lasted four to seven weeks. Few studies reported beneficial outcomes that would be regarded as clinically relevant.
Key results
Four small studies reported that pain was reduced by between a quarter and a third in some people. This level of pain reduction was experienced by 6 in 10 participants with morphine and 4 in 10 with placebo. Between 1 and 2 in 10 participants withdrew from treatment with both morphine and placebo, but the reasons were not given. Side effects were poorly reported, but were more common with morphine than with placebo, and included drowsiness, dizziness, constipation, feeling sick, dry mouth, and decreased appetite.
Quality of the evidence
The evidence was of very low quality. This means that the research did not provide a reliable indication of the likely effect, and the likelihood that the effect will be substantially different is very high. Small studies like those in this review tend to overestimate results of treatment compared to the effects found in larger, better designed studies. There were other problems that might lead to over-optimistic results. The very low quality evidence and the lack of any important benefit mean that we need new, longer-lasting, large trials before we will know if morphine is useful for the treatment of neuropathic pain.
Authors' conclusions:
There was insufficient evidence to support or refute the suggestion that morphine has any efficacy in any neuropathic pain condition.
Background:
Neuropathic pain, which is caused by a lesion or disease affecting the somatosensory system, may be central or peripheral in origin. Neuropathic pain often includes symptoms such as burning or shooting sensations, abnormal sensitivity to normally painless stimuli, or an increased sensitivity to normally painful stimuli. Neuropathic pain is a common symptom in many diseases of the nervous system. Opioid drugs, including morphine, are commonly used to treat neuropathic pain. Most reviews have examined all opioids together. This review sought evidence specifically for morphine; other opioids are considered in separate reviews.
Objectives:
To assess the analgesic efficacy and adverse events of morphine for chronic neuropathic pain in adults.
Search strategy:
We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and Embase for randomised controlled trials from inception to February 2017. We also searched the reference lists of retrieved studies and reviews, and online clinical trial registries.
Selection criteria:
We included randomised, double-blind trials of two weeks' duration or longer, comparing morphine (any route of administration) with placebo or another active treatment for neuropathic pain, with participant-reported pain assessment.
Data collection and analysis:
Two review authors independently extracted data and assessed trial quality and potential bias. Primary outcomes were participants with substantial pain relief (at least 50% pain relief over baseline or very much improved on Patient Global Impression of Change scale (PGIC)), or moderate pain relief (at least 30% pain relief over baseline or much or very much improved on PGIC). Where pooled analysis was possible, we used dichotomous data to calculate risk ratio (RR) and number needed to treat for an additional beneficial outcome (NNT) or harmful outcome (NNH). We assessed the quality of the evidence using GRADE and created 'Summary of findings' tables.
Main results:
We identified five randomised, double-blind, cross-over studies with treatment periods of four to seven weeks, involving 236 participants in suitably characterised neuropathic pain; 152 (64%) participants completed all treatment periods. Oral morphine was titrated to maximum daily doses of 90 mg to 180 mg or the maximum tolerated dose, and then maintained for the remainder of the study. Participants had experienced moderate or severe neuropathic pain for at least three months. Included studies involved people with painful diabetic neuropathy, chemotherapy-induced peripheral neuropathy, postherpetic neuralgia criteria, phantom limb or postamputation pain, and lumbar radiculopathy. Exclusions were typically people with other significant comorbidity or pain from other causes.
Overall, we judged the studies to be at low risk of bias, but there were concerns over small study size and the imputation method used for participants who withdrew from the studies, both of which could lead to overestimation of treatment benefits and underestimation of harm.
There was insufficient or no evidence for the primary outcomes of interest for efficacy or harm. Four studies reported an approximation of moderate pain improvement (any pain-related outcome indicating some improvement) comparing morphine with placebo in different types of neuropathic pain. We pooled these data in an exploratory analysis. Moderate improvement was experienced by 63% (87/138) of participants with morphine and 36% (45/125) with placebo; the risk difference (RD) was 0.27 (95% confidence interval (CI) 0.16 to 0.38, fixed-effects analysis) and the NNT 3.7 (2.6 to 6.5). We assessed the quality of the evidence as very low because of the small number of events; available information did not provide a reliable indication of the likely effect, and the likelihood that the effect will be substantially different was very high. A similar exploratory analysis for substantial pain relief on three studies (177 participants) showed no difference between morphine and placebo.
All-cause withdrawals in four studies occurred in 16% (24/152) of participants with morphine and 12% (16/137) with placebo. The RD was 0.04 (-0.04 to 0.12, random-effects analysis). Adverse events were inconsistently reported, more common with morphine than with placebo, and typical of opioids. There were two serious adverse events, one with morphine, and one with a combination of morphine and nortriptyline. No deaths were reported. These outcomes were assessed as very low quality because of the limited number of participants and events.
http://www.cochrane.org/CD011669/SYMPT_morphine-neuropathic-pain-adults
