PainJournal.net
Clinical Journal of Pain for
Healthcare Professionals and Patients
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PainJournal.net Clinical Journal of Pain for Healthcare Professionals and Patients
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CHRONIC PAIN - NEW APPROACHES TO EFFECTIVE PAIN MANAGEMENT LEADS TO BETTER LIFESTYLE John Krusz, M.D., Ph.D.
Physicians and other health care providers who treat patients in pain have grappled with defining this universal phenomenon. What is pain? At its simplest level, I would define pain as “Anything that hurts”. The International Association for the Study of Pain (IASP) has a more formal definition: “Pain: An unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage”. One of the giants in the field of pain management, John Bonica, once said: “Pain is a major human concern influencing every aspect of life: it is the most common symptom of disease which compels patients to seek medical counsel. Whereas acute symptomatic pain serves the useful purpose of warning the individual of something wrong and is a useful diagnostic aid for the physician, in its chronic pathologic form, pain is a malefic force which often imposes severe emotional, physical, and economic stresses on the patient, on his family, and on society....” In practical terms, acute pain is distinguished from chronic pain in several ways: with acute pain, there is an adequate and definable stimulus for the production of the symptom. An example would be inflammatory pain secondary to a burn. This is also termed nociceptive pain. With chronic pain, however, the original provoking factor is often no longer apparent; rather, the person complains of their painful symptom without any obvious determinable cause. An example of this type of pain would be a complex regional pain syndrome (CRPS), formerly called reflex sympathetic dystrophy. But, absence of cause is not absence of problem! The transition from acute to chronic pain takes time, and is a very complicated physiologic process involving many different neuropeptides and neurotransmitter systems in the dorsal horn of the spinal cord. This is a key aspect of the production and maintenance of persistent pain states. Arbitrarily, a chronic pain condition is one where the symptoms have persisted more than 6 months. How prevalent is chronic pain? Other than headache, which affects 90 million people in the US, chronically painful conditions affect 75-80 million people. Arthritic disorders, low back and neck pain, cancer, and neuropathic pain disorders form the bulk of this huge group of people afflicted and often disabled with pain. The cost to society is staggering: millions of lost workdays per month, severely blunted performance on the job, a lot of lost time from family and personal activities. The total cost is in the hundreds of billions of dollars when you add it all up. At the best, many people simply live with their pain and endure many restrictions in their activities. At the worst, they are totally disabled and unable to care for themselves and impose a large drain on their families and on the medical system that attempts to care for them. Either way, better treatment options would dramatically improve the pain patient’s ability to function and have a better lifestyle. And that’s the good news aspect of this brief review. We have many revolutionary new approaches to managing pain states and many more that will emerge in the next few years. As a pain and headache specialist, I look forward to being able to offer newer treatments to my patients with each passing year. Research in pain mechanisms has grown tremendously and has elucidated exciting new mechanisms for pain control. Let’s look at some of the exciting developments: Classically, pain control was accomplished with opiates. These are derivatives or congeners of morphine, the reference pain medication originally found in and extracted from the poppy plant. Morphine and other opiates act on mu receptors in the nervous system. Indeed, by now, everyone has heard of endorphins.These are a system of neuropeptides made by our nervous system and are devoted to preventing the transmission of painful messages and to inhibiting the sensation of pain. Actually, morphine and other opiates act on a system of three major opiate receptors, mu, kappa, and sigma, each with slightly different properties. Although opiates can attenuate a painful condition, acute or chronic, their good effects are accompanied by a host of undesirable properties such as constipation, euphoria and, worst of all, the property of tolerance. This means that the same dose which produced a good reduction to pain will no longer do so effectively. Therefore, the dose must be raised to re-establish the effect which, in turn, leads to more side effects and so on. Most clinicians confuse tolerance with addiction. Addiction refers to a person’s behavior and not at all to the pharmacologic properties of a molecule! While it is true that opiates produce tolerance to their effects and can lead to a biochemical state of physical dependence this too is confused with “addiction”. Once again, addictions refer to behavior, not to the properties of a molecule! Opiates have been lifesaving in many painful disorders. Although they are most easily accepted as treatment for cancer-related pain, there is still a form of stigma associated with using opiates for non-cancer pain states. Physicians fear the draconian efforts of the DEA and tend to underprescribe these agents for fear of reprisals from administrative agencies. Also, because there exists the possibility of recreational use by a small number of drug-seeking individuals posing as “patients”, this tends to be generalized onto any legitimate pain patient who derives real pain relief from opiates. The Texas Pain Society has put forth a far-reaching set of statements (called the Texas Pain Initiative) which outline the role of opiates in any chronic pain state, cancer-related or not. It has served as model for a number of other states’ pain prescribing guidelines enacted in their legislatures. I am proud to be a member of the Texas Pain Society. Lets move on from the opiate system. We recognize that it is but one of many systems in the body that put the brakes on pain transmission. The spinal cord, especially the dorsal horn, and many areas in the brainstem act as relay stations and filters for incoming pain signals trying to get to sensory recognition areas in the brain’s cortex. When a painful train of signals has successfully outpaced the various inhibitory systems in the spinal cord and brainstem and has negotiated its way past the main sensory processing complex of the brain, the thalamus, the person then has the perception of pain. Responses to chronically painful stimuli are evoked in many other brain areas, particularly those associated with memory processing and those linked to other emotionally charged experiences, often referred to as the limbic system. Besides the endorphin systems, there are two multi-purpose molecules that nature has found useful to keep around: norepinephrine (NE) and serotonin (5HT). These neurotransmitters are both involved in a descending set of pain inhibiting pathways that help the endorphin system to impede pain transmission in the spinal cord. I use the terms ascending and descending loosely, to denote pain signals trying to get to the brain and systems that tend to put the brakes on this process, respectively. An example of a compound that acts at all three places (opiate receptor, NE and 5HT) in the spinal cord or brain is tramadol, a most useful medication for chronic pain and headaches. One subset of NE receptors is called the alpha2 receptor and it also resides on nerve cells in the dorsal horn of the spinal cord. One recently introduced agent, tizanidine, acts only at alpha2 receptors and has marked pain and headache reducing properties, according to studies I have done in the last two years. Another system used in nervous tissue involves receptors, or places where a drug can exert its effect, for excitatory amino acids. These are mainly glutamic and aspartic acid, although the former has been better characterized and studies so far. Glutamate has several receptor subtypes, but the one that gets the most attention in pain circles is the NMDA (N-methyl-D-aspartate) type of glutamate receptor. This system opposes the effects of opiates and may play a key role in the formation of tolerance when opiates are used chronically, according to recent research reports. In a sense, the action of glutamate receptor activation promotes the transmission of pain. There are also other glutamate receptor subtypes (AMPA-type and kainate) which may modulate pain transmission in nervous tisssue. One of the newest so-called anticonvulsants, topiramate, blocks the non-NMDA type of glutamate receptor as one of its actions. A fundamental property of nerve cells is that they fire when they reach threshold for their action potential. This is largely driven by sodium ions, although calcium also plays a strong role in permitting a state of readiness for repetitive firing. We know that local anesthetics have the pharmacologic property of blocking sodium channels in nerve trunks and this how they prevent firing of signals down the axon to the next connecting neuron. All of our older anticonvulsants (read neuronal stabilizers) like phenytoin, carbamazepine, divalproex sodium and the newer lamotrigine and topiramate have sodium channel blockade as the main, or a major, mechanism of action. And guess what? They all have the ability to tone down neuropathic, or nerve trunk, pain. Another gating or braking set of mechanisms are accomplished by salts that are present in every cell in the body; namely, calcium and magnesium. With the former, too much activity may be a bad thing. We know that excessive calcium release can be injurious or fatal to nerve cells. There are a number of ways to block the effects of calcium. The most physiologic approach would be through magnesium, which opposes the actions of calcium in many places in the nervous system. I utilize this principle for controlling acute muscle spasm and headaches in the pain clinic via intravenous doses of magnesium. This will often get rid of muscle spasm and headaches very rapidly. It has no side effects, is very inexpensive and can save a pain or headache sufferer’s day. In fact, we now know that the brains of people with headaches are deficient in magnesium, so it makes sense that flooding the nervous system with the salt might reverse the symptoms. Likewise, calcium excess is associated with muscle contraction, high blood pressure and many other negative processes in the body. The calcium channel blockers have proliferated into 4 major types: L,N,P and T. They don’t exist in the same places in the nervous system or in various organs of the body. The most common use medically for calcium channel blockers is to control high blood pressure. Other members of this class do many interesting things; for example, flunarizine, a compound available for many years in Canada and Europe, not only is an anticonvulsant but is also quite good as migraine preventative agent. One very interesting compound, formerly called SNX-111 and now named ziconotide has been shown to be a very powerful pain relieving agent, some 1000 times more potent than morphine! Without the usual downsides of opiates like tolerance. Ziconotide was originally found in toxins made by fish-hunting sea snails. It strongly blocks an N-type calcium channel, presumably in the spinal cord. The N-type channels are thought to be the ones responsible for controlling release of neurotransmitters in nervous tissue. This is an exciting new way to think about inhibiting the transmission of painful stimuli trying to get to the brain. One of my favorite neurotransmitter inhibitory systems is called Gamma-amino-butyric acid or GABA for short. This, too, is not a single receptor type but rather a family of related (but probably distinct) receptors. GABA is the most prevalent inhibitory neurotransmitter in the central nervous system. It is manufactured from the excitatory amino acid glutamate, a potential bad guy as described earlier in this article. GABA prevents nerve cells from firing and that is how it accomplishes its inhibitory mission. There is one subtype of GABA receptor, called GABAA, which seems to be very important in headache and other kinds of pain. I have found that a specific drug, called propofol, can eliminate headache and other kinds of pain. This medication only acts on GABAA receptors and nowhere else. Other new agents, which I like to call neuronal stabilizers, also act on the GABAA receptor in part. An excellent example is topiramate, an anticonvulsant which has anti-pain and anti-headache properties. These are very exciting developments and may open the way for a whole new set of pain and headache treatments. So, that’s the whole current menu of things we can attack to reduce pain. There will be many more in the near future, as pain research shows us where to look further. Stay tuned.
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