Today's post from consultqd.clevelandclinic.org (see link below) talks about a new advance in stem cell therapy concerning mesenchymal stem cells (MSC). These have been shown to reduce nerve pain and if they are injected directly into the vein, they have also been shown to reduce the side effects and addictiveness of opioids. Of course it's not as simple as this but these wonder cells apparently also can travel to the site of nerve injury and repair nerve cells on the spot. It may all seem a bit sci-fi and magical but it is true and reveals the huge potential of stem-cell therapy for all sorts of medical issues in the future. The fact that mesenchymal stem cells (MSC) directly apply to neuropathy problems makes it an exciting development for nerve pain patients across the world. Now we have to find the money in state budgets to develop the science and insurance companies who will pay for the treatment - don't hold your breath.
Stem Cell Therapy for Neuropathic Pain: New Findings Show Promise
Animal studies demonstrate effectivenessAug. 10, 2016 / Pain Management / Research
Stem cell research at Cleveland Clinic could pave the way for an entirely new approach to chronic pain treatment that reduces medicine’s current reliance on opioid therapy for intractable pain. The modality also shows promise as a tool to reverse opioid tolerance (OT) and opioid-induced hyperalgesia (OIH), particularly problematic side effects of opioid therapy. Jianguo Cheng, MD, PhD, and his colleagues at Cleveland Clinic have developed patented methods of attenuating opioid tolerance.
Animal studies by Dr. Cheng and his colleagues have demonstrated the effectiveness of mesenchymal stem cell (MSC) transplantation in reducing hyperalgesia due to nerve injury. The group’s work has shown MSC transplantation’s effectiveness in reducing pain induced by sciatic nerve injury in rats and mice. MSC transplantation significantly reduced pain sensitivity evaluated by foot withdrawal thresholds in animals in response to thermal or mechanical stimulation. These cells produced immune modulatory and anti-inflammatory effects, promoted sensory nerve repair, and showed strong analgesic properties that could provide a safer and more effective alternative to current treatment modalities, in the management of neuropathic pain, says Dr. Cheng, Professor of Anesthesiology and Director of the Cleveland Clinic Multidisciplinary Pain Medicine Fellowship Program.
Pain medicine researchers are searching for an alternative to opioid therapy because neuropathic pain often does not respond to morphine and other opioids. Opioid analgesics can also lead to a variety of complications, ranging from itching and constipation to dependence, addiction, respiratory depression and death.
About 30 percent of neuropathy cases are caused by nerve damage associated with diabetes. However, hundreds of diseases are linked to neuropathic pain. Sources of neuropathic pain include alcoholism, amputation (which can result in phantom pain), some chemotherapy drugs (for example, Cisplatin®, Paclitaxel®, Vincristine®), radiation therapy, complex regional pain syndrome type II, trigeminal neuralgia, shingles, spinal stenosis, and central nervous system disorders, such as Parkinson disease and multiple sclerosis.
Recent research by Dr. Cheng and his group has yielded new discoveries that bode well for MSC transplantation as a potential future treatment modality. One investigation compared the analgesic effects of MSC derived from bone marrow with MSC derived from adipose tissue. Adipose-derived cells were found to be as efficacious as bone marrow-derived cells in reducing neuropathic pain in rats. The finding suggests that stem cell therapy could offer a practical option because stem cells from adipose tissue are relatively easy to obtain.
Recent investigations by Dr. Cheng and his colleagues comparing the analgesic effectiveness of intrathecal versus intravenous methods of MSC transplantation show both methods to be equally effective. The finding has important implications because intravenous transplantation of MSC could offer a safer and more expeditious route of delivery than intrathecal transplantation.
“We originally thought that stem cells would have to be introduced intrathecally in order to reduce pain, and that stem cells introduced intravenously would pass through the lungs and fail to produce analgesia,” says Dr. Cheng. “The finding that intravenous transplantation is as effective as intrathecal transplantation is encouraging.”
Dr. Cheng’s group has also discovered that MSCs can be found in the area surrounding the injured nerve following MSC transplantation. “For reasons we do not yet fully understand, these cells have the ability to migrate to the injury site to promote repair of the injured nerve fibers,” Dr. Cheng says. “The cells can sense the injury’s location and travel to it.”
Although many questions must be answered before it can be known whether stem cell therapy is safe and effective for humans, some small patient studies show potential, Dr. Cheng says. According to one observational study in Australia, MSC transplantation reduced pain in patients suffering from trigeminal neuralgia, a particularly difficult condition to treat. “Though the findings are preliminary, the study provides some evidence that what we have learned in the laboratory can be translated to clinical use,” Dr. Cheng says.
Dr. Cheng’s team has achieved analgesia with MSC transplantation from rats to mice, providing early evidence that stem cells’ anti-inflammatory and immuno-modulatory properties can be transferred between species. An important pre-clinical study will be to see whether the transplantation of human stem cells to animals also can produce analgesic and anti-tolerance effects, Dr. Cheng says.
Dr. Cheng’s team presented research at the 2016 annual meeting of the American Academy of Pain Medicine showing MSC’s potential to reverse opioid tolerance and opioid-induced hyperalgesia, problems that can compromise the safety and efficacy of opioid therapy. Intravenous transplantation of bone marrow-derived MSC significantly attenuated OT and OIH in animals whether the transplantation was performed seven days before or 14 days after the initiation of daily morphine injections. These data demonstrate that MSC transplantation can not only prevent the development of OT and OIH but can also reverse it.
https://consultqd.clevelandclinic.org/2016/08/stem-cell-therapy-neuropathic-pain-new-findings-show-promise/
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
