Progress Report 2008: Pain
The 2008 Progress Report on Brain Research


February, 2008

Pain is the number one reason people seek medical care in the United States. Yet physicians continue to struggle to find effective means of treating and managing both chronic and acute pain.

Pain researchers took several approaches in 2007. Some sought ways to reduce addiction to powerful opioid drugs, which are often the most effective means of providing pain relief. Others identified a crucial pain-signaling pathway that opens new avenues of treatment for patients suffering from significant “phantom” pain following a spinal cord injury. Still others found a more effective treatment for chronic neuropathic pain, offering hope to millions of people who suffer from disabling back pain.

Chronic Pain and Opioid Addiction

For several thousand years, opium has been used to relieve pain and suffering, and many drugs derived from opium, called opioid drugs, are used today for both legitimate and illegitimate purposes. The tendency of these drugs to cause addiction because of their powerful euphoric effect has created a conflict for physicians, who must balance the patient’s need for pain relief against the risk of causing dependency.

Although chronic pain diminishes the analgesic effect of many opioid drugs, researchers at Wake Forest University School of Medicine have found that it also weakens an individual’s tendency to become addicted to some of these drugs, including morphine, hydromorphone, and fentanyl. The findings, which appeared in the February 27, 2007, issue of Anesthesiology, suggest that if chronic pain is not treated adequately with appropriate drugs, patients eventually will stop taking prescribed drugs and seek alternatives, including heroin and methadone, that are more effective at treating chronic pain but that have the feared addictive consequences.1

The Wake Forest researchers implanted catheters in rats, half of which had their spinal nerves ligated, or twisted, and then trained them to self-administer clonidine and adenosine, two drugs that effectively reverse hypersensitivity to pain. The researchers found that neither drug had any effect on heroin-seeking behavior in normal rats, because, they say, sites in the brain and not the spinal cord mediate the abuse potential of heroin in a normal animal.

In rats with chronic pain, however, the researchers found that administering clonidine into the spine drastically reduced heroin-seeking behaviors. The administration of adenosine at the spinal level did not affect heroin-seeking in the injured rats, even though this drug is known to alleviate hypersensitivity to pain after nerve injury. These findings suggest, at least in the animal model, that both clonidine and adenosine given together can produce pain relief without producing the urge to use heroin.

Another study revealed that a subgroup of chronic pain patients is prone to addictive drug-seeking behavior. Researchers at Massachusetts General Hospital examined several studies to determine how opioid addiction relates to chronic pain relief. The researchers reported in the journal Pain in June that early assumptions that addiction would be rare among patients treated for chronic pain were incorrect.2 Rather, drug-seeking and other negative behaviors do occur in a small group of chronic pain patients. How addiction starts, however, is different for this subgroup. Specifically, in this subgroup, the transition to addiction is subtler and more difficult to identify.

Although physicians are armed with a wealth of information that can help prevent opioid addiction when treating patients with chronic pain, the researchers say better tools are needed to help determine who among these patients is likely to become addicted. Physicians, they add, can then develop structured treatment regimens with support from addiction specialists, which may require using alternatives to opioid drugs.

Pain Signal Targeting

Nearly 80 percent of people who suffer a spinal cord injury develop clinically significant pain, describing it as burning, aching, shooting, or stabbing. In addition, many patients who have lost feeling in some parts of their bodies suffer from phantom pain in which they “feel” the body below the spinal cord lesion and experience pain in these areas of total sensory loss.

A dysfunction of the nervous system causes the abnormal pain that often develops following spinal cord injury, say scientists at the Yale University Center for Neuroscience and Regeneration Research. The researchers reported in the February 28, 2007, issue of the Journal of Neuroscience that they had demonstrated for the first time a direct signaling pathway in the injured spinal cord between neurons and microglia, immune cells that reside in the central nervous system and mount an inflammatory response to protect the nervous system, but at times may actually damage it.3

Using adult rats that underwent spinal cord contusion injury, the researchers found that a molecule called prostaglandin E2 (PGE2) is central in microglia-mediated chronic pain. This molecule is released by activated microglia and contributes to the sensitization of spinal neurons after injury.

Targeting this microglia-neuron signaling mechanism, the Yale researchers say, may lead to successful pain management following spinal cord injury. The researchers are examining compounds that block the signaling pathway at several sites in the spinal cord. The prototype compound is minocycline, an antibiotic approved by the Food and Drug Administration to treat a number of infections, which is also in clinical trials to test its effectiveness in currently “off-label” uses to treat several neurological disorders, such as Huntington’s disease, amyotrophic lateral sclerosis, and multiple sclerosis.

The Yale team is using a type of imaging called positron emission tomography to attempt to verify evidence that a similar, if not identical, pain mechanism exists in both humans and mice. If so, they will test the effectiveness of minocycline in patients with spinal cord injury in shutting down the PGE2 pain signaling mechanism.

Effective Back Pain Relief with Neurostimulation

Back pain is one of the most common medical problems in the United States, affecting about 80 percent of the population at some point in their lives. According to a Duke University study in 2004, back pain—in the form of lower back pain, neck pain, or sciatica—costs the United States nearly $100 billion per year in medical bills, disability payments, and lost productivity. Although conventional therapies and surgery have proved somewhat effective at reducing back pain, researchers have found that neurostimulation, a treatment that employs an implantable medical device to deliver electrical impulses, is better at relieving chronic neuropathic pain in the back and legs. These electrical impulses are sent to the epidural space in the spinal column in order to keep pain signals from reaching the brain.

In the largest multi-center, randomized, controlled trial of neurostimulation to date, an international consortium of researchers, led by Krishna Kumar of Regina General Hospital in Canada, found that neurostimulation provides better pain relief, quality of life and functional capacity than conventional treatments, such as pain drugs, pharmaceutical nerve blocks, steroid injections, physical therapy, and chiropractic care.

The study, published in Pain in November, found that six months after treatment, nearly half the patients who received neurostimulation along with conventional treatments experienced an improvement in leg pain at least 50 percent greater than the improvement reported by people who received only conventional therapy.4 Each of the patients had undergone at least one back surgery for a herniated disk but continued to experience moderate to severe pain in one or both legs and in the back at least six months after their surgery.

Because disabling neuropathic pain is difficult to treat, the researchers say neurostimulation should be added to the list of treatments routinely offered to patients who suffer chronic back pain.

On the West Coast, physicians at Coast Pain Management in California reported in the July Neuromodulation that a specific type of neurostimulation called peripheral nerve field stimulation is a safe and effective alternative for patients with chronic low back pain.5 The physician-scientists examined the effectiveness of this treatment in six patients with chronic low back pain with whom conventional therapies were unsuccessful. In contrast to spinal cord or direct peripheral nerve stimulation, peripheral nerve field stimulation uses leads placed through the skin and into the area of pain to stimulate the region of the affected nerves. In each of the six patients, they reported, peripheral nerve field stimulation allowed a reduction in pain medication and an increase in activity level, along with higher quality of life.

Peripheral nerve field stimulation has distinct advantages over other forms of neurostimulation, including fewer complications and lower morbidity, according to the researchers, who say that this treatment shows promise as a complement to existing therapies and deserves further study.

Notes

1. Martin TJ, Kim SA, Buechler NL, Porreca F, and Eisenach JC. Opioid self-administration in the nerve-injured rat. Anesthesiology 2007 106(2):312–322.

2. Ballantyne JC and LaForge KS. Opioid dependence and addiction during opioid treatment of chronic pain. Pain 2007 129(3):235–255.

3. Zhao P, Waxman SG, and Hains BC. Extracellular signal-regulated kinase-regulated microglia-neuron signaling by prostaglandin E2 contributes to pain after spinal cord injury. Journal of Neuroscience 2007 27(9):2357–2368.

4. Kumar K, Taylor RS, Jacques L, Eldabe S, Meglio M, Molet J, Thomson S, O’Callaghan J, Eisenberg E, Milbouw G, Buchser E, Fortini G, Richardson J, and North RB. Spinal cord stimulation versus conventional medical management for neuropathic pain: A multicentre randomized controlled trial in patients with failed back surgery syndrome. Pain 2007 132(1–2):179-188.

5. Paicius RM, Bernstein CA, and Lempert-Cohen C. Peripheral nerve field stimulation for the treatment of chronic low back pain: Preliminary results of long-term follow-up: A case series. Neuromodulation 2007 10(3):279–290.

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