Chronic nagging back pain can result from spinal cord injury (SCI) and can lead to pain in other parts of the body that are in fact not injured. It can be very difficult to diagnose and a person suffering from it can find their quality of life seriously compromised. I know, for I have been suffering from such pain for three months now and only this week have I been able to put together a diagnosis and identify an effective treatment plan for myself. There are two stories to be told here. One is a science story about a new paradigm for viewing and treating chronic neuropathic pain and the other is a personal story about how I managed to connect the dots about my personal problem and arrive at insight as to what is going on in me. I relate the science story here.
Neuropathic pain is pain “gone wild,” normally pain that was initiated by some injury to the nervous system but that assumes a life of its own and is out of proportion to the original injury and can show up in other locations. It creates “allodynia, meaning “other pain”, a pain due to a stimulus which does not normally provoke pain(ref).” “As much as 7% to 8% of the population is affected by neuropathic pain and in 5% it may be severe(ref)(ref)(ref).” Neuropathic pain may result from a variety of conditions including injuries to or disorders of the peripheral nervous system or the central nervous system (brain and spinal cord).
The traditional view of pain is that it is caused by firing of neurons which transmit signals up to the brain. The conventional way to handle even persistent neuropathic pain has therefore been to block the neural signals. This approach has a basic limitation. Opiates like morphine are the most effective drugs for blocking acute pain. But in the case of chronic pain opiates seem to become less and less effective in time requiring the use of higher doses leading to addiction. “Previous studies have shown opiates to be relatively ineffective for neuropathic pain in animals, and the animals typically develop tolerance over a short period of time, in that the drugs lose their ability to relieve pain(ref).”
In the mid-90s a new view of neuropathic pain started to emerge, which is to pay attention to the glial cells, the microglia and astrocyte cells which accompany and support the neurons in nervous tissues in the spine. Before pain is perceived in the brain, pain-producing signals must pass through stages of neural circuitry including ones that pass through the spine. There are more glia than neurons in the spinal cord and brain and they play essential functions like providing nourishment to neurons, maintaining the chemical environment surrounding neurons and absorbing neurotransmitter molecules given off by them. Glia listen carefully to signaling molecules from the neurons they accompany and respond with signaling molecules of their own. This mutual molecular signaling process serves many important functions, including facilitating repair of damaged nerves. However, it can get out of control and produce neuropathic pain.
Quoting from a 2004 paper Glial activation: a driving force for pathological pain “Pain is classically viewed as being mediated solely by neurons, as are other sensory phenomena. The discovery that spinal cord glia (microglia and astrocytes) amplify pain requires a change in this view. These glia express characteristics in common with immune cells in that they respond to viruses and bacteria, releasing proinflammatory cytokines, which create pathological pain. These spinal cord glia also become activated by certain sensory signals arriving from the periphery. Similar to spinal infection, these signals cause release of proinflammatory cytokines, thus creating pathological pain. Taken together, these findings suggest a new, dramatically different approach to pain control, as all clinical therapies are focused exclusively on altering neuronal, rather than glial, function.” An excellent and detailed explanation of this new view is in the article New Culprits in Chronic Pain in the November 2009 issue of Scientific American. This 2009 paper further explains the molecular biology of how activated microglia creates pain without apparent cause (allodynia).
A simplified explanation is that neurons respond to an injury by firing rapidly to signal pain and releasing stress-related messenger molecules. These changes are picked up by the microglia which begin emitting molecules that ease stress on the neurons and increase their sensitivity. Among these molecules are proinflammatory cytokines like Interleukin-1, TNFÎ± and IL-6, and TNFr, urgent messengers requesting mobilization of the body’s repair mechanisms. The cytokines can greatly increase the sensitivity of the injured neurons as well as other neighboring neurons causing them to fire all the more. This in turn leads to additional production of cytokines by neighboring microglia, etc. A vicious pro-inflammatory cycle ensues. As this happens the pain is amplified. Further, the cytokines fan out and affect other tissue systems leading them to give out their own pain signals. The result is neuropathic pain – pain amplified in the nervous system.
“Pathological pain has long been described as the result of dysfunctional neuronal activity. While neuronal functioning is indeed altered, there is significant evidence showing that exaggerated pain is regulated by the activation of astrocytes and microglia. In exaggerated pain, astrocytes, and microglia are activated by neuronal signals including substance P, glutamate, and fractalkine. Activation of glia by these substances leads to the release of mediators that then act on other glia and neurons. These include a family of proteins called “proinflammatory cytokines” released from microglia and astrocytes. These cytokines have been shown to be critical mediators of exaggerated pain. Some patients with pathological pain also report “extra-territorial” and/or “mirror” image pain (Allodynia). That is, exaggerated pain is experienced not only in the area of trauma. In extra-territorial pain, pain is also perceived as arising from neighboring healthy tissues outside of the site of trauma. In the rare cases of mirror-image pain, such pain is perceived as arising from the healthy, corresponding body part on the opposite side of the body. New data suggest that activation of astrocyte communication via gap junctions may mediate such spread of pain(ref).”
The paper Activated Microglia Contribute to the Maintenance of Chronic Pain after Spinal Cord Injury probably tells the central story of my own pain experience “Given that there are data supporting the involvement of microglia in pain after peripheral injury and work showing chronic post-SCI activation of microglia, we hypothesized that activated spinal microglia play a role in chronic central pain after SCI. Here, we report that thoracic SCI causes chronic activation of microglia in the lumbar spinal cord and that these activated microglia contribute to the maintenance of neuronal hyperresponsiveness and pain-related behaviors.”
The new view of pain also explains why opiates like morphine lose their pain-killing effectiveness in time(ref). It turns out that since morphine or other opiates lowers the sensitivity of neurons to pain, the accompanying glia whose job is to maintain balance detect that fact and send out proinflammatory molecules that ratchet the neuron’s sensitivity back up again. So, the blunting effect of the narcotic on pain is unblunted. The agony of withdrawal experienced by a heroin addict who suddenly stops taking the drug is also explained. While on the drug, the addicted person’s microglia have ratcheted up the pain sensitivity of the person’s neurons so that the person’s pain sensitivity is restored to near normal. Suddenly withdrawing the drug leaves the person’s pain neurons super-sensitized without the blunting effect of the narcotic and it takes several days for them to calm back down.
The way to treat chronic pain according to this new perspective is to inhibit microglia from expressing cytokines, a story told by the title of the 2009 paper Early microglial inhibition preemptively mitigates chronic pain development after experimental spinal cord injury. “These results suggest that inhibition of early neuroimmune events can have a powerful impact on the development of long-term pain phenomena following SCI and support the conclusion that modulation of microglial signaling may provide a new therapeutic strategy for patients suffering from post-SCI pain.” One of the first substances identified that calm down microglia is the drug minocycline. “The current study examined the hypothesis that early administration of the microglial-inhibiting drug minocycline could ameliorate the development of pain after SCI. — Adult male Sprague-Dawley rats underwent SCI at the ninth thoracic spinal segment and received either vehicle or minocycline treatment for 5 days postinjury. Time course studies revealed that over 4 weeks post-SCI, microglial activation in vehicle-treated animals was progressively increased. Minocycline treatment resulted in reduction, but not prevention, of microglial activation over time. — These results suggest that inhibition of early neuroimmune events can have a powerful impact on the development of long-term pain phenomena following SCI and support the conclusion that modulation of microglial signaling may provide a new therapeutic strategy for patients suffering from post-SCI pain.”
The aforementioned Scientific American article mentions nine different of drugs being tested for their capability to quiet overactive glia, either in cell or animal tests and in some cases in clinical trials. But that article says nothing about any drug that is available right now that quiets glia and is generally safe to use on a protracted basis for neuropathic pain. Through serendipity I believe I have possibly identified such a substance, a familiar drug Gabapentin (Neurontin). Indeed, I have been using this drug and in the course of four days it has brought my pain level down from 7-8 to 1-3 and greatly enhanced my comfort and functionality.
Gabapentin, is widely prescribed for chronic spinal pain and other pain conditions though its means for controlling pain have not been understood. Gabapentin is approved by the FDA as an anti-convulsive drug and only for the Post-Therapeutic Neuralgia pain indication. Neurontin has an interesting history. While several scientific studies and clinical trials support its use for pain management and a large percentage of the prescriptions for Neurontin are off-label, the company owning the rights to it, Pfizer, has gotten into trouble for promoting such uses. “A division of Pfizer Inc., the world’s largest drug maker, has agreed to plead guilty to two felonies and pay $430 million in penalties to settle charges that it fraudulently promoted the drug Neurontin for a string of unapproved uses(ref).” And there are still many unsettled lawsuits connected with such uses. The key point here is that, strictly speaking, Gabapentin is an off-label treatment for neuropathic pain. Moreover, the drug is now a low-cost generic so it is unlikely that Pfizer would ever want to incur the high costs of clinical trials for other indications.The 2003 review paper Gabapentin dosing for neuropathic pain: Evidence from randomized, placebo-controlled clinical trials concludes “At doses of 1800 to 3600 mg/d, Gabapentin was effective and well tolerated in the treatment of adults with neuropathic pain.” The 2005 review paper Gabapentin in the treatment of neuropathic pain states: “Clinically, several large randomized controlled trials have demonstrated its effectiveness in the treatment of a variety of neuropathic pain syndromes. Patients with neuropathic pain can expect a mean reduction in pain score of 2.05 points on an 11 point numerical rating scale compared with a reduction of 0.94 points if they had taken the placebo. Around 30% of patients can expect to achieve more than 50% pain relief and a similar number will also experience minor adverse events –.“ The 2004 paper Gabapentin is a first line drug for the treatment of neuropathic pain in spinal cord injury and the paper Gabapentin effect on neuropathic pain compared among patients with spinal cord injury and different durations of symptoms report on studies suggesting that Gabapentin may be particularly effective for treating neuropathic pain associated with spinal cord injuries.
The paper I have found that suggests that Gabapentin moderates pain via the microglia is Gabapentin reverses microglial activation in the spinal cord of streptozotocin-induced diabetic rats. “In addition, an attenuation of microglial activation correlated with reduced Allodynia following Gabapentin treatment, while Gabapentin had no effect on the number of astrocytes. Here we show a role of microglia in STZ-induced mechanical Allodynia and furthermore, that the anti-Allodynia effect of Gabapentin may be linked to a reduction of spinal microglial activation. Astrocytic activation in this model appears to be limited and is unaffected by Gabapentin treatment. Consequently, spinal microglial activation is a key mechanism underlying diabetic neuropathy. Furthermore, we suggest that Gabapentin may exert its anti-allodynic actions partially through alterations of microglial cell function.”
While this last conclusion is based on experiments with pain due to induced spinal injury in rats, I suspect strongly it also applies to spinal neuropathic pain in humans. I have found a number of other papers suggesting possible molecular channels through which Gabapentin may inhibit pain, related to Gabapentin and cytokines and how Gabapentin inhibits the expression of NF-kappaB in certain cells, but none others that directly deal with the effects of Gabapentin on microglia.
I am on day 4 of Gabapentin treatment and the pain/discomfort level due to my spinal injury is running 1-3 in a scale of 1 to 10, down from a month or more of 6-8. Time will tell whether I can maintain this comfort level and whether the original injury will heal. So, I now have: 1. a good working diagnosis of my condition; it is neuropathic pain created by a probably-minor spinal injury incurred while swimming, 2. what so far is an effective therapeutic regimen, 3. a significantly enhanced personal state of comfort and functionality associated with pain reduction, and 4. an understanding of the basic mechanisms of the pain that was torturing me, as explained in this blog entry.
Get well soon!
Thanks Res. You are a real supporter.
See this for your back – worked brilliantly for my.
Great blog you’ve got – I found you via your post on hormesis
Thanks for your suggestion. I will definitely try the exercise. I have an excellent physical therapist who does all kinds of stresses on my upper and middle back and gives me stress exercise. The idea that they work by a kind of hormesis is new to me but quite natural wnen I think about it. My MRI shows “severe spinal stenosis” in C5 and C6 cervical regions. However between the physical therapy and the galbapentin my pain/discomfort level has gone down from as much as 8-9 to 1 in the last several days. Welcome to the blog!
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My spinal cord pain and issues have been completely cleared up for over two years as of now (June 27, 2012). I attribute this to regular exercise including back flex exercises and to supplements I am taking, particularly curcumin and omega 3 fatty acids.
A June 26 2012 study:
Dietary therapy to promote neuroprotection in chronic spinal cord injury
Laboratory investigation (http://thejns.org/doi/abs/10.3171/2012.5.SPINE1216) reports:
“Object: The pathogenesis of cervical spondylotic myelopathy (CSM) is related to both primary mechanical and secondary biological injury. The authors of this study explored a novel, noninvasive method of promoting neuroprotection in myelopathy by using curcumin to minimize oxidative cellular injury and the capacity of omega-3 fatty acids to support membrane structure and improve neurotransmission.
An animal model of CSM was created using a nonresorbable expandable polymer placed in the thoracic epidural space, which induced delayed myelopathy. Animals that underwent placement of the expandable polymer were exposed to either a diet rich in docosahexaenoic acid and curcumin (DHA-Cur) or a standard Western diet (WD). Twenty-seven animals underwent serial gait testing, and spinal cord molecular assessments were performed after the 6-week study period.
At the conclusion of the study period, gait analysis revealed significantly worse function in the WD group than in the DHA-Cur group. Levels of brain-derived neurotrophic factor (BDNF), syntaxin-3, and 4-hydroxynonenal (4-HNE) were measured in the thoracic region affected by compression and lumbar enlargement. Results showed that BDNF levels in the DHA-Cur group were not significantly different from those in the intact animals but were significantly greater than in the WD group. Significantly higher lumbar enlargement syntaxin-3 in the DHA-Cur animals combined with a reduction in lipid peroxidation (4-HNE) indicated a possible healing effect on the plasma membrane.
Data in this study demonstrated that DHA-Cur can promote spinal cord neuroprotection and neutralize the clinical and biochemical effects of myelopathy.”