How Mediators Drive Chronic Pain

How Mediators Drive Chronic Pain

When asked how pain occurs, most people will answer that it is a simple process in which something damages your body and a nerve impulse is sent to the brain. While this vague outline is generally true, it is vastly inadequate in describing the intricate cascade of events involved in pain phenomena. Much has been discovered in pain mechanisms in recent years, but one of the most intriguing is pain mediators which play an essential role in pain signaling.

Modern Epidemic of Chronic Pain

Chronic pain is any pain condition that persists for longer than three months.  It has been estimated that chronic pain is common to 20 percent of the U.S. adult population, with 8 percent experiencing high-impact pain that interferes with daily activities. These pain issues not only cost the American public more than $560 billion each year in medical costs, lost productivity and disability programs, but they are an enormous burden on the patients and their families emotionally.

This epidemic of chronic pain has also spawned another public health crisis—rampant opioid abuse.  One study by Neurometrix found that almost 62 percent of the American public was taking or had taken opioids for chronic pain. In past years, doctors have over-prescribed opioids for pain which has led to addiction, overdoses and deaths. From one-fifth to one-third of patients prescribed opioids will misuse them, and 8 to 12 percent will develop a use disorder.

In 2018, there were almost 47,000 opioid overdose deaths in the U.S., a byproduct of the estimated 1.7 million Americans currently suffering from an opioid-related substance use disorder.  This problem has slightly declined in the most recent years, however, as the medical establishment has adopted more stringent standards for prescribing opioid medications.

Emerging Research into Pain Mediators

Although the number of opioid-related overdoses and deaths appear to be on the decline, there is still the issue of managing severe chronic pain. Due to aggressive oversight and an overabundance of caution, physicians are much more reluctant to dole out opioids, even to those with a clear medical need. This has prompted the biomedical research industry to investigate alternatives to opioid medications.

Among the most promising fields of pain medication research is pain mediators. In order to understand what mediators are and why they are of such enormous interest to the pharmaceutical industry, you must have a basic understanding of pain transmission in the human nervous system.  When an injury or illness damages a part of the body, a sensory receptor or nociceptor will generate a nerve impulse.  This impulse will propagate along the axon of the nerve cell via sodium and potassium ions that are managed with channels traversing the neuron’s cell wall.

The impulse is relayed to the spinal cord neurons through the release of neurotransmitters by the primary neuron. These neurotransmitters include the amino acid glutamate and the neuropeptide substance P. The neurotransmitter will bind to receptors on the secondary neuron which, if sufficient in strength, will open ion channels for admitting calcium ions. This spinal cord secondary neuron will transmit the pain signal to the brainstem which, in turn, relays it to the cortex.

The brain plays several roles in processing pain. First of all, it locates the pain and assigns an intensity.  The brain also replays similar pain experiences in an effort to generate a mitigation strategy. It also attaches emotions like fear and stress so that you pay more attention to the hurtful stimuli.

If the damage to the body is intense or prolonged, the primary sensory nerve may release a large amount of mediator neurotransmitters. This may cause the spinal nerve to generate more receptors for neurotransmitters on its surface. This proliferation of receptors makes it more sensitive to pain impulses and is called central sensitization. Normally, when the damage is repaired, this sensitization will disappear and the spinal nerve will reset; however, some chronic pain conditions are characterized by ongoing central sensitization.

How Some Therapies Interfere with Pain Signal Transmission

It seems obvious, then, that pain treatments should focus on blocking the release of neurotransmitters from primary afferent neurons or their binding to secondary neurons.  Some drugs act in this way, including morphine which both interferes with mediator release and receptor binding.  Anticonvulsant drugs like gabapentin and pregabalin limit the release of neurotransmitters.

Another way of interfering with pain signal transmission is radiofrequency rhizotomy with involves killing nerve cells with electrical heat; the primary afferent neuron is usually the target. A similar technique known as glycerol rhizotomy uses glycerol injected into a nerve to damage its ability to conduct a nerve impulse. Stereotactic radiation precisely irradiates a nerve in order to create a lesion that interferes with signal transduction.

Neural stimulation has also proven effective at blocking pain signals. The more common form of this therapy is spinal cord stimulation which applies a low-strength electrical current to a region of the spine.  This current activates the nerves in the area, preventing them from receiving pain impulses or transmitting them on.

A less common form of neural stimulation is deep brain stimulation. DBS also involves a low-voltage current, but this is applied to the pain processing centers of the brain.  This pain management technique has proven effective in 80 percent of patients, with pain cut by 50 percent on average.

There is also some intriguing new research that suggests that pain receptors on nerve cells may migrate into the cell. If confirmed, this could explain why many chronic pain patients develop a resistance to pain medications.

New therapies that are coming online are targeting the NK1R receptor that initiates a neuron’s pain signal. Unlike other drugs that have targeted the NK1R receptor and failed because they couldn’t penetrate the cell wall, new pain medications have a fat component that allows them to pass into the cell. Once inside, the drug will attach to the NK1R receptor and shut down pain signal generation. Current studies using these kinds of drugs have already proven successful, at least, among rat subjects.

Article written by: Dr. Robert Moghim – CEO/Founder Colorado Pain Care

M.D. Disclaimer: The views expressed in this article are the personal views of Robert Moghim, M.D. and do not necessarily represent and are not intended to represent the views of the company or its employees.  The information contained in this article does not constitute medical advice, nor does reading or accessing this information create a patient-provider relationship.  Comments that you post will be shared with all visitors to this page. The comment feature is not governed by HIPAA and you should not post any of your private health information.