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1. The Physiology Of Pain
Pain is deﬁned as ‘an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage.’ It is the most common complaint voiced by patients when they seek medical attention. The ability to perceive pain serves a protective function for the individual. The sensation warns of impending injury and elicits reﬂex and behavioral responses that keep tissue damage to a minimum (see Livingston 1998, Melzack 1973, Rey 1995).
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In many instances, noxious stimuli applied at the skin surface (blunt trauma, burns, a surgical incision) serve to activate pain receptors. These are special nerve cells, termed nociceptors, which convert (transduce) the energy delivered at the periphery to neural impulses. Transduction is the ﬁrst of four processes allowing the energy that produces noxious stimuli to result eventually in the perception of pain. Once this initial energy is transduced into electrical impulses, nerves carry the stimulus to higher levels of the nervous system. This activity is termed trans-mission, and it allows the noxious stimuli to be conveyed from the skin to the spinal cord as a series of electrical messages. As the signals arrive in the dorsal horn of the spinal cord, they are altered by other impulses within the cord and by descending impulses from higher neural centers. This is termed modulation. These modiﬁed and processed impulses continue upward towards the brain and allow a person to experience the perception of pain. This is an individual and highly subjective phenomenon. Another person can not reliably measure it. There is no objective appraisal of the sensation that an individual calls pain.
An understanding of the four events is critical to an appreciation of the mechanisms by which pain can be managed. The physician targets therapies to prevent the electrical signals from reaching the cortex and limbic systems of the brain where pain enters a person’s consciousness. Thus treatments are aimed at interrupting pain information as they are transduced to nerve impulses; transmitted towards the spinal cord; and modulated within the cord; or by modifying the neural impulses as they enter the brain where the actual perception occurs.
Minimizing the pain a patient perceives has value on a number of fronts: humanitarian, physiologic, functional, and economic. Progress made in this area of medicine was begun by anesthesiologists in the 1980s when they began to organize services to treat surgical inpatients immediately following operations. These activities were logical extensions of the work they already performed during surgery. Acute pain services are now well established divisions of most hospitals in the United States.
Workers in the ﬁeld of pain management divide pain into three separate categories: acute, chronic non-malignant, and cancer pain. Management varies depending on the etiology. Acute pain is experienced following trauma, elective surgical procedures, or the exacerbation of chronic medical conditions (e.g., sickle cell crisis). Tissue damage initiates a cascade of physiological and behavioral changes. These have the potential to progress into chronically painful states if left unattended.
1.1 Acute Pain
Mechanisms to manage operative and postoperative pain focus on the delivery of medications to speciﬁc sites within the body. Local anesthetics, such as lidocaine can be injected under the skin prior to an incision. This is exempliﬁed by the use of a nerve ﬁeld block performed immediately before an inguinal hernia repair. The medication is injected at the site of the surgery and given time to work. Local anesthetics act by blocking the conduction of impulses down nerve ﬁbers. These nerves, then, cannot transmit to the central nervous system (CNS) the information that tissue damage (the surgical incision) is occurring. Since the CNS never receives the nerve impulses, the patient does not perceive pain.
More sophisticated techniques include the deposition of local anesthetics into areas wherein numerous nerves converge. Because these areas are densely packed with passing nerve ﬁbers, a small amount of anesthetic can eﬀectively block pain messages from a large segment of the body. Examples of these procedures include brachial plexus (an area of convergent nerves from the arm and hand) blockade prior to hand surgery, and epidural (a space just outside the spinal cord) blockade, which is used to blunt the intensity of labor pains prior to childbirth. One problem of the use of local anesthetic is that these agents are generally fairly short-acting. The duration of the blockade can be prolonged by co-injection of agents which decrease blood ﬂow in the immediate area of injection. Less blood ﬂow to the area of blockade means the anesthetic agent is taken away by the bloodstream more slowly, prolonging the presence, and eﬀect, of the local anesthetic. Another method physicians use to prolong local anesthetic action is to pump anesthetic continuously into the needed area through a plastic tube or catheter that has been inserted into that region. This technique allows pain control for very long periods of time. For example, a catheter placed in a position that blocks pain from the chest (thorax) can be used to manage pain related to chest (thoracic) surgery for ﬁve days following the operation. A catheter is placed at the appropriate level within the epidural space and taped to the patient’s skin. An infusion pump is programmed to deliver local anesthetic, opioid (such as morphine), or a mixture of both agents at an hourly rate. When the mixture of agents is used, very dilute concentrations of each are employed. Inhibiting the transmission and modulation of nerve impulses with diﬀerent classes of agent allows for synergy of eﬀect. Excellent control of very strong pain can be achieved with the use of epidural catheter placement and the constant infusion of analgesic mixtures. Sensitivity of the aﬀected area returns quickly when the drugs are stopped.
Unfortunately, local anesthetics block not just pain sensors, but all nerves. Thus, they produce a profound numbness and, in some cases, diﬃculty in moving muscles. In addition, they are only active for a short time, or require the placement of a catheter near the nerves to be aﬀected. Therefore, other means are necessary to deal with more long-duration pain. For example, systemic medications can be delivered intravenously to blunt the perception of pain. Newer technology in the form of microprocessors and physically small infusion pumps have made the management of acute, post-surgical pain more precise. Patient-controlled analgesia (PCA) pumps provide an infusion of morphine or similar drugs at a constant background rate. This is usually 1 or 2 milligrams of morphine over the course of an hour. Furthermore, a patient can activate the pump to deliver additional morphine by the push of a button. Dosage is often 2 milligrams which can be repeated every sixth minute. This machinery allows the patient substantial control of how much morphine he or she is receiving so that the dose delivered matches his or her needs. The background infusion guarantees that some analgesia is delivered to the bloodstream to compensate for normal clearance of the analgesic by the liver and kidneys. The patient-controlled aspect enables the patient to raise immediately the blood level of the morphine should the perception of pain increase in intensity. This commonly correlates with the patient’s degree of physical activity and can often be anticipated. A patient who is comfortable while lying down may feel pain when getting into a chair. In this instance, self-dosing permits the level of opioid to match the need for analgesia on a minute by minute basis. Since the pump must be activated before delivering additional medication, the risk of overdosage is minimized. Patients who are sleepy from a high serum level of morphine will not push the button for additional medication. In some instances, morphine is not the appropriate agent to use as it produces signiﬁcant side-eﬀects in some patients. In these cases, other opioids such as fentanyl, demerol, or dilaudid can be used. Individual preferences and the reactions to treatment are used to guide further therapy.
Progress has been made in the development of nonsteroidal, anti-inﬂammatory drugs (NSAIDs). Aspirin, acetomenophin, and ibuproﬁn are well known examples of these drugs. NSAIDs are a class of medications that diminish swelling and decrease the perception of pain. They act both at painful sites and in the CNS by inhibiting the enzyme cyclo-oxygenase. Intramuscular and intravenous NSAIDs have been developed so that patients in the immediate postoperative period and still unable to consume pills can beneﬁt from the agents. The newest drugs in the class are highly selective for the desired eﬀects and show little of the side eﬀects which have been problems with the long-established NSAIDs. Patients are often offered intravenous doses of an NSAID in the postoperative period if they experience pain breaking through despite continuous epidural infusion of local anesthetics (see above).
New approaches to delivering analgesic drugs into the body are also being developed. Intranasal (nasal spray), pulmonary (inhaler), and transbuccal (under the tongue) routes of opioid delivery are all being researched with the goal of providing immediate pain relief. A transdermal system of the opioid fentanyl delivery is currently available but is rarely used to treat acute pain. The skin directly under the sticky transdermal patch absorbs fentanyl which acts to gradually release the medication over hours or even days. Unfortunately, changing the blood level of a drug is slow when using transdermal patches, and so the risk of drug overdose in this patient population is higher. Transdermal patches are rarely used in the postoperative phase of patient care, but are more commonly used for chronic and cancer-related pains.
1.2 Chronic Pain
Chronic, noncancer related pain aﬀects 75 million Americans. Pain decreases the quality of life of these people and impairs their ability to work productively. Chronic pain is deﬁned as pain that persists for longer than the expected time frame for healing, or pain associated with progressive diseases. Many patients suﬀer from clinical syndromes for which there are no x-ray, laboratory, or other physical evidence of something wrong, and so diagnoses rely on clinical criteria alone. These syndromes include many kinds of headache, myofascial pain syndromes (for example chronic jaw pain), ﬁbromyalgia, neuropathic pain, low back pain, and central pain syndromes. Little is known about the underlying causes of these syndromes. Patients do, however, present with the complaint of pain. Other patients have disorders that are well described, e.g., osteoarthritis, but for which we have no cure.
Irrespective of the cause, the eﬀects of chronic pain on a patient’s life tend to be more pervasive than that of acute pain. Chronic pain aﬀects all of the patient’s social relationships, personality, and mood. Typically, people with chronic pain tend to have sleep disturbances, generalized fatigue and a decrease in their overall level of functioning. In many, the perception of pain cannot be eliminated, only lessened. The goal becomes one of managing the pain as well as is possible while improving the person’s involvement and function in his life. To this end, a multidisciplinary approach that focuses on all aspects of the patient’s condition seems to have the best results. The core team consists of a pain management specialist along with representatives from pharmacy, physical and occupational therapy, psychology, and internal medicine. The care team tailors the care plan according to the needs of the individual patient. An open discussion of goals is necessary to assess objectively if progress is being made. Often the goals of productive activity and a return to work are stressed.
Treatment of chronic, non-cancer related pain conditions requires the use of analgesic medications. NSAIDs are often the mainstay of therapy. Long-term use of the agents carries the risk of easy bruising, renal dysfunction, and the development of gastric ulcers. As mentioned above, the newer NSAIDs help to limit these side eﬀects. Patients must be warned of these complications and followed closely. The agents are potent analgesics that improve the quality of life for those who suﬀer from many chronic pains, especially arthritis.
Long-acting opioids can eﬀectively control pain in a subset of chronic pain patients. Patients must be assessed carefully before the start of therapy. The potential for substance abuse or addiction must be considered even though they are not commonly encountered in patients with chronic pain. Guidelines exist which help to clarify the conditions under which the prescribing of opioids is appropriate in the treatment of chronic pain states. Common adverse side eﬀects include constipation, pruritis, sedation, and impaired cognition. Although most of the side eﬀects diminish over time, constipation usually persists and must be treated.
Antidepressants are eﬀective in the treatment of many painful conditions. Their mechanism of action is unclear, but they seem to act by increasing the levels of norepinephrine and serotonin at the nerve synapses of the central nervous system. In addition to their direct eﬀect in diminishing the perception of pain, the agents also are useful as an aid to sleep. Patients take the medication in the late evening and report improvements in their ability to fall asleep and stay asleep throughout the night. The agents have the potential for bothersome side eﬀects which include dry mouth, blood pressure changes, urinary retention, and, rarely, heartbeat irregularities. The drugs are used as a part of an integrated care plan and improve the overall quality of the patient’s life.
Anticonvulsants are eﬀective in the treatment of many chronic pain states. The mechanism of action is again unclear. They may suppress the production of nerve impulses in nerve cells that are critical in developing the perception of pain. A newer anticonvulsant, gabapentin, provides symptomatic relief with fewer side eﬀects than older drugs of this class. Patients notice sedation and episodes of dizziness when they begin taking the drug, but acclimate to it over a matter of days.
More invasive methods for the treatment of chronic painful states have been tried with no proven beneﬁt. Cutting the spinal cord pathways that transmit pain messages to the brain produces temporary (6–12 month) pain relief, but the pain then returns, sometimes worse than ever. The direct injection of local anesthetics into the most painful muscle areas of myofascial pain syndrome seems to provide symptomatic relief for some of the patients. The procedures have not been tested in a randomized or blinded manner, however, and the beneﬁts may be the result of the placebo reaction. Epidural steroid and local anesthetic injections have also been used for those who complain of vague lower back pains. The steroids are known to decrease inﬂammation, edema, and decrease the synthesis of prostaglandins (substances known to mediate the perception of pain). Again, the patients often report beneﬁts in their symptoms, but there is no clear mechanism to explain the improvement.
1.3 Cancer Pain
The prevalence of cancer pain ranges from 30–50 percent of patients who are undergoing active treatment for solid tumors. The number climbs to 80–90 percent for those who suﬀer from advanced forms of the disease. Approximately three-quarters of these chronic pain syndromes result as a direct eﬀect of the tumors themselves. The remaining complaints are related to the therapies administered to manage the primary or metastatic aspects of the cancer.
Neoplastic (tumor) invasion of bone or connective tissue is a major cause of severe pain. The spine is the most common site of bony metastasis. Many patients with cancer have back pain because the cancer has spread to this bony area. Continued growth of the tumor causes spinal cord and nerve root compression. Cancerous growth in this area will result in pain, as well as paralysis and the loss of bowel and bladder control for the patient. Obstruction and compression of the bowel produces intense visceral complaints. Patients will present with persistent abdominal pain, constipation, nausea, and vomiting. The tumor will have to be surgically removed, sometimes resulting in nerve injury-induced (neuropathic) pain. Radiation, frequently used to shrink tumors, can cause ﬁbrosis, which may in turn damage peripheral nerve and central nervous system tissue. These injuries frequently cause a chronic neuropathic-type pain, along with tingling and numbness in the area.
The mainstay for management of cancer-related pain is the use of oral analgesics leading up to opioids in progressively larger doses as the disease progresses. The World Health Organization has devised an algorithm for use of oral analgesics that matches the intensity of the pain with the potency of the medication prescribed. Although the oral route is commonly used, the transdermal approach has gained popularity because of the ease of administration. Each patch is worn for approximately three days before it must be replaced. The system has the advantage of infrequent dosing, but as mentioned above, keeping the right blood level is diﬃcult. Most practitioners will start the patient with a relatively low dose of transdermal fentanyl, but then give the patient morphine pills to use as needed in order to supplement the relief provided by the patch. Individualization is the key to successful treatment. Each patient must be evaluated and a treatment plan formulated based on that individual’s needs. In some, radiation and chemotherapy will eﬀectively reduce the tumor mass and diminish pain. In others, there will be little hope of shrinking the tumor and the only recourse is to make these patients as comfortable as possible. This ‘end-of-life’ strategy is termed palliative care.
The success of continuous infusions of local anesthetics in the operating room and immediately postoperatively has prompted the developments of portable and reprogrammable infusion pumps for use by cancer pain patients. In some cases, these pumps are implanted under the skin. Pumps allow the continuous infusion of strong opioids through catheters to sites directly within the spinal canal, either epidurally or directly onto the spinal cord itself (intrathecally). The opioids act directly on nerve cells in the spinal cord to inhibit pain messages, resulting in profound pain relief. The epidural or intrathecal catheters are tunneled under the skin and attached to a pump that has within it a reservoir to hold the opioid. The machinery is programmed to deliver a preset amount of opioid as needed to provide adequate pain relief. On a regular basis, the reservoir is reﬁlled to allow for continuous pain relief as needed.
The most invasive therapies used for those with advanced stages of cancer involve the use of ablative surgical or anesthetic procedures. As mentioned above, spinal cord incisions can produce profound pain relief. Because pain recurs over the long term, however, this procedure is only used near the end of life. Pure alcohol is toxic to nerves. Thus, another fairly drastic procedure involves the injection of pure alcohol into individual nerves of the spinal cord to destroy those nerves carrying pain messages to the CNS. In these ways, patients near the end of their life can achieve a degree of pain relief that is not attainable with less invasive measures.
Cancer pain must be viewed in the context of a progressively advancing illness. The optimum management allows for the treatment to match the intensity of discomfort. The smallest dose of the most benign medication that provides relief is used ﬁrst. When the intensity of pain increases, stronger medications and more invasive techniques are used. In this way, a comprehensive range of agents and techniques are used in sequence to provide optimal pain relief.
2. Novel Approaches To The Relief Of Pain
Recent laboratory studies have shown that transplantation of adrenal medullary tissue or of isolated chromaﬃn cells into CNS pain modulatory regions can reduce pain sensitivity in both acute and chronic (including neuropathic) models in rats. The analgesia produced by these transplants probably results from the release of both opioid peptides and catecholamines such as adrenaline and noradrenaline since it can be blocked or attenuated by both opiate and adrenergic blockers. Studies indicate that even over long periods there is no apparent development of tolerance.
Positive results have also been obtained in preliminary clinical studies using transplants of human adrenal gland pieces to relieve intractable cancer pain in 25 patients. Pain scores and morphine intake were measured prior to transplantation and at regular intervals following the graft implantation. Biochemical assays were performed on a sample of the patients’ cerebrospinal ﬂuid (CSF) throughout the study to assess levels of catecholamine and met-enkephalin (an opiate manufactured by the body) as an indication of graft viability. Sixteen out of 20 patients reported long lasting pain relief from these transplants (more than a year in some patients). Narcotic analgesic (e.g., morphine) intake was eliminated, reduced or at least stabilized in all patients who completed the study. These studies indicate that even over long periods, there is no development of opiate tolerance. Histological data was obtained at autopsy from some patients who had transplants for over a year. Study of the spinal cord revealed intact adrenal medullary tissue fragments distributed over several levels, with no signs of inﬂammation or rejection. The results of these clinical trials are encouraging over all and suggest that chromaﬃn cell transplants can provide relief from intractable pain. With appropriate modiﬁcations to optimize graft preparations and survival, it is likely that this approach can become an alternative means of controlling pain refractory to traditional pharmacotherapies (see Michalewicz et al. 1999, Lazorthes et al. 2001).
2.2 Gene Therapy
Another new approach to chronic pain is that of gene therapy. This method so far is only at the animal testing stage, but appears to be very promising. Diﬀerent approaches have been taken to change the genetics of nerve cells that are involved in pain so that that function of the cells is disrupted. The ﬁrst of these involves the injection of ‘antisense’ on to the spinal cord. Genes are essentially codes that cells read, and which cause the cell to make a particular chemical, as, for example, a protein. Some of these chemicals are critical to the transmission of pain information from one cell to another. Antisense is essentially the code for one of these chemicals, but in reverse order. This eﬀectively disrupts the cell’s ability to read the ‘real’ gene and so inhibits its ability to make the chemical. If antisense is injected on to surface of the spinal cord, some of it will ﬁnd its way into the correct pain neurons and so, to a greater or lesser extent, inhibit transmission of pain messages (see Peric et al. 2001).
Applying antisense to spinal cord nerve cells appears to work in animals, but is somewhat nonselective as to which cells it goes into, and is not very eﬃcient in getting it there. For this reason, other researchers have been working on ways to use viruses as ‘vectors’ to carry genes that may inhibit pain transmission into the nerve cells that carry that information. One method involves putting the gene for naturally-occurring opioids into either adenoviruses (the kinds that causes the common cold) or herpes viruses (the kinds that causes cold sores). These viruses are very eﬃcient at getting these genes into spinal nerve cells and produced long-lasting analgesia in animals. The adenovirus is injected directly into the spinal cord itself, whereas the herpes virus is placed near pain receptors outside the CNS where it is taken up and carried back to the spinal cord. The herpes virus approach has also been used to carry antisense directly into the pain-conducting nerves (see Wilson et al. 1999). All of these approaches present new and exciting approaches to the treatment of chronic pain.
- Lazarthes Y, Bes J C, Sol C, Pappas C D 2001 Intrathecal chromaﬃn cell allograﬀ for cancer pain. In: Burchiel (eds.) Surgical Management of Pain. Thieme Medical Publishers Inc., New York, pp. 973–9
- Livingston W K 1998 Pain and Suﬀ IASP Press, Seattle, WA
- Melzack R 1973 The Puzzle of Pain. Basic Books, New York
- Michalewicz P, Laurito C E, Pappas G D, Yeomans D C 1999 Puriﬁcation of adrenal chromaﬃn cells increases autinociception eﬃciency of xenotransplants in the absence of immunosuppression. Cell Transplant 8: 103–9
- Peric V, Lu Y, Laurito C E, Yeomans D C 2001 Combined eﬀects of N-type calcium channel blockers and morphine on a-delta US. C ﬁber mediated nociception. Anesthesiology and Analgesia 92: 39–243
- Rey R 1995 The History of Pain. Harvard University Press, Cambridge, MA
- Wilson S I, Yeomans D C, Beuder M A, Lu y, Glorioso J 1999 Antihyperalgesie eﬀects of delivery of encephains to mouse nociceptive neurons by herpes virus encoding proeucephalins. Proceeding of the National Academy of Sciences of the USA 96: 3211–16