No announcement yet.

Chronic Pain Management Paradigm: Time for a Change? - Medscape Article

  • Filter
  • Time
  • Show
Clear All
new posts

    Chronic Pain Management Paradigm: Time for a Change? - Medscape Article

    Chronic Pain Management Paradigm: Time for a Change? CME
    Author: Steven Simon, MD, RPh

    Complete author affiliations and disclosures are at the end of this activity.

    Release Date: May 26, 2004; Valid for credit through May 26, 2005

    Target Audience

    This activity is intended for pain clinicians (neurologists, internists, family practicians, primary care providers, and rheumatologists), nurses, and pharmacists.

    The goal of this activity is to provide clinicians with an understanding of the management of chronic nonmalignant pain and breakthrough pain.
    Learning Objectives
    Upon completion of this activity, participants will be able to:

    1. Identify critical psychologic and physiologic factors that affect pain management.
    2. Illustrate the major processes related to the pathophysiology of pain.
    3. Describe traditional and novel pharmacologic interventions for chronic nonmalignant pain and breakthrough pain.

    Credits Available
    Physicians - up to 1.0 AMA PRA category 1 credit(s);
    Pharmacists - up to 1.0 contact hour(s) (0.1 CEUs);
    Registered Nurses - up to 1.0 Nursing Continuing Education contact hour(s)

    All other healthcare professionals completing continuing education credit for this activity will be issued a certificate of participation.

    Participants should claim only the number of hours actually spent in completing the educational activity.

    Canadian physicians please note:
    CME activities that appear on are eligible to be submitted for either Section 2 or Section 4 [when creating a personal learning project] in the Maintenance of Certification program of the Royal College of Physicians and Surgeons, Canada [RCPSC]. For details, go to
    Accreditation Statements

    For Physicians

    Medscape is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.

    Medscape designates this educational activity for a maximum of 1.0 category 1 credit(s) toward the AMA Physician's Recognition Award. Each physician should claim only those credits that reflect the time he/she actually spent in the activity.

    For questions regarding the content of this activity, contact the accredited provider for this CME/CE activity: For technical assistance, contact

    For Pharmacists

    1.0 contact hour(s) (0.1 CEUs) of credit for pharmacists. Approval of this course for pharmacists is under a cosponsorship agreement between Medical Education Collaborative, Inc. (MEC) and Medscape. MEC is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. ACPE # 815-999-04-002-H01.

    For questions regarding the content of this activity, contact the accredited provider for this CME/CE activity: For technical assistance, contact

    For Nurses

    Approved for 1.0 contact hour(s) of continuing education for RNs, LPNs, LVNs and NPs. This activity is cosponsored with Medical Education Collaborative, Inc. (MEC) and Medscape. MEC is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's Commission on Accreditation.

    Provider approved by the California Board of Registered Nursing, Provider Number CEP 12990, for 1.0 contact hour(s).

    Approved by the Florida Board of Nursing, Provider Number FBN 2773.
    Instructions for Participation and Credit

    This online activity is formatted to include text, graphics, and may include other multi-media features. There are no fees for participating and receiving credit for this activity.

    Participation in this self-study activity should be completed in approximately 1.0 hour(s). To successfully complete this activity and receive credit, participants must follow these steps during the period from May 26, 2004 through May 26, 2005.

    1. Make sure you have provided your professional degree in your profile. Your degree is required in order for you to be issued the appropriate credit. If you haven't, click here. For information on applicability and acceptance of continuing education credit for this activity, please consult your professional licensing board.
    2. Read the target audience, learning objectives, and author disclosures.
    3. Study the educational activity online or printed out.
    4. Read, complete, and submit answers to the post test questions and evaluation questions online. Participants must receive a test score of at least 70%, and respond to all evaluation questions to receive a certificate.
    5. When finished, click "submit."
    6. After submitting the activity evaluation, you may access your online certificate by selecting "View/Print Certificate" on the screen. You may print the certificate, but you cannot alter the certificate. Your credits will be tallied in the CME Tracker.

    This activity is supported by an unrestricted educational grant from Cephalon - Actiq.

    Legal Disclaimer
    The material presented here does not reflect the views of Medical Education Collaborative, Medscape or the companies providing unrestricted educational grants. These materials may discuss uses and dosages for therapeutic products that have not been approved by the United States Food and Drug Administration. A qualified health care professional should be consulted before using any therapeutic product discussed. All readers or continuing education participants should verify all information and data before treating patients or employing any therapies described in this educational activity.

    Contents of This CME Activity

    1. Chronic Pain Management Paradigm: Time for a Change?
    Case Example
    The Universe of Pain
    Understanding the Analgesics
    Opioids -- The Fear Factor
    Reading the Signals
    The Painful Personality
    Physiologic Consequences of Acute Pain
    The Psychology of Suffering
    The Traditional Paradigm
    The New Paradigm

    Chronic Pain Management Paradigm: Time for a Change?

    "Pain," according to John Milton, "is perfect misery, the worst of evils, and excessive, overturns All patience."

    Chronic pain deprives those who suffer of the ability to participate in the day-to-day activities that fulfill their lives, destroying their basic enjoyment of life. Despite scientific advances in the understanding and management of pain and a growing awareness of and willingness to utilize pain management options among healthcare providers, relief from pain continues to elude many patients. The appropriate use of pain medication ultimately can restore the enjoyment of life to our patients.

    This review discusses the current approaches to pain management and suggests a change in the paradigm for chronic pain management, revising concepts of breakthrough pain. We examine the pitfalls in managing chronic noncancer pain, discuss the physiologic and psychologic consequences of chronic noncancer pain, and describe the various types of pain. Next, we review the mechanisms of pathology and treatment options with pharmacologic and nonpharmacologic therapies for chronic noncancer pain, and finally, discuss the role of opioids in the treatment of chronic nonmalignant pain.

    Case Example

    Patricia S. is a 58-year-old hospice nurse with a history of mastectomy for breast cancer 7 years ago with no recurrence. Around the same time, she was diagnosed with fibromyalgia. Her pain was well controlled with amitriptyline and an exercise regimen until she suffered an acute, work-related shoulder injury. A work-up of her shoulder demonstrated no tears or broken bones, and she was diagnosed with a shoulder sprain complicated by bursitis.

    Her orthopaedist prescribed a course of physical therapy and naproxen. The initial pain subsided slowly but never completely resolved. In particular, she noted that even though the pain was not severe, she had trouble finding a comfortable position in bed and, as a result, did not sleep well most of the time. In addition, she was afraid that her shoulder pain would flare up if she returned to her previous exercise regimen and, as a result, the fibromyalgia-associated discomfort returned.

    Her primary care physician raised the bedtime amitriptyline dose and prescribed extended-release oxycodone in addition to the naproxen for the pain. The new regimen enables her to sleep through the night, although she does not feel refreshed when she wakes up in the morning. She also complains of feeling "fuzzy headed" in the morning. Moreover, she is still reluctant to exercise or work around the house, fearing that lifting regular household items above shoulder level will cause a flare-up. She certainly cannot take care of her infant grandson or participate fully in work-related activities. She notes that after a full day at work, even when her duties are confined to giving out medications, her pain returns full force, and even if she takes a dose of oxycodone, she has to rest for at least an hour before she can begin fixing dinner.

    Her primary care provider is considering raising the dose or increasing the frequency of the oxycodone. Patricia is beginning to worry that her pain may be a symptom of something much more serious than bursitis.

    The Universe of Pain

    Pain has been called an ageless, universal phenomenon -- an unpleasant, multidimensional sensory experience that delivers wide variations in intensity, quality, duration, and persistence.[1] The experience of pain combines strong physical, cognitive, and emotional components. In addition to suffering, these physiologic components include avoidance motor reflexes and alterations in autonomic output. As a heterogeneous sensory entity, pain results from a variety of mechanisms. Moreover, there are several different types of pain, including nociceptive, inflammatory, neuropathic, and functional.[2]

    Much pain is self-limiting; however, sometimes the pain does not recede, festering instead into chronic suffering. Chronic noncancer pain is generally defined either as pain that has been present for at least 6 months longer than expected or pain resulting from a condition in which there is ongoing nociception or neuropathic pain.[3] However, the reasons that other, nonmalignant pain becomes chronic are not entirely clear.

    Anxiety associated with the phenomenon of pain is another important component of the experience. A recent Dutch study[4] found an association between the fear of pain and the perception of disability in a population of patients with chronic low back pain. This supratentorial element is what makes the experience of pain different from one person to the next and underscores the importance of examining the whole patient in our approach to pain relief, to look at why and how each patient hurts as we seek to remove his or her pain. In the time span between the occurrence of pain and achieving pain relief lie the seeds of suffering. Suffering begins when patients are waiting for the pain medicine to act.

    Understanding the Analgesics

    Careful and thoughtful selection of pharmacologic agents and the correct dosing, including both the timing and concentration of the medication, are not easy decisions. Analgesic agents can have unique properties; those characteristics can aid in the selection of the best agent to treat the specific pain of the presenting patient.

    The first step in the process is to understand the pharmacology of these preparations and how they are cleared by the body. Will their metabolism affect the metabolism of other medications? For example, many of the drugs used to treat pain, especially the hydrophilic opioids, are processed by the 2D6 system. People of North African descent and people of Mediterranean descent often do not have this enzyme.[5] Fentanyl, on the other hand, is a lipophilic agent that is processed metabolically by the 3A4 system, which is different from the 2D6 system.

    A wide variety of options is available among commercially available analgesic preparations. The choice depends on the desired location, intensity or strength, and timing of the onset of action, including the so-called "immediate-release" agents, which are really short-acting compounds, and the "controlled-release," or longer-acting medications.

    The classes of analgesics are further divided into 3 broad categories: the nonopioids, the adjuvants, and the opioids. Nonopioids include acetaminophen and the nonsteroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen. The adjuvants are a wide-ranging class of drugs that have primary indications other than for pain relief -- anticonvulsants, antidepressants, and antispasmodics. Because they have the capacity, in general, to penetrate the blood-brain barrier and alter nociception, they can be highly analgesic for certain patients in certain circumstances. Thus far, opioid agents have been used infrequently outside the cancer arena (and even within the cancer arena).

    Figure 1. A conceptual approach to pain treatment.

    In the setting of chronic pain, our best choice for effective analgesia is most often an agent that acts not only on the local area of the pain, but also affects the patient's perception of and response to that pain (Figure 1). Thus, opiate agents may be the best choice for relief of chronic nonmalignant pain, such as that associated with arthritis. Opioid drugs are effective at blocking the nociceptive pain signal from the periphery to the central nervous system; they can alter the patient's perception of pain, and can ease suffering by improving the patient's overall sense of well-being by improving his or her physical function and restoring sleep.

    Opioids -- The Fear Factor

    The conflict between the physicians' desire to ease pain and their fear of causing addiction[6] by the use of opioids has endured through many decades. Because of the specter of addiction, many have suffered needlessly, even those with intractable pain at the end of life. More recently, however, opioid therapy has rebounded in popularity as an invaluable and accepted treatment for acute cancer-related pain and pain caused by a terminal disease.

    The related question of whether and how to prescribe opioid therapy for chronic pain that is not associated with terminal disease remains contentious.[3,7,8]

    Despite the recognition that opioid therapy can relieve pain and improve mood and functioning in many patients with chronic pain, and the recommendations by experts that such patients be treated with opioids,[9,10] many physicians continue to be reluctant to prescribe them.[11]

    These opioid-resistant physicians have argued that opioids possess only marginal utility for improving the quality of life of patients with chronic pain and may actually make matters worse.[8] However, this seems to be a minority view. Consensus statements from major groups with experience and expertise with patients who have chronic pain strongly support the use of opioids to treat chronic pain.[12,13] These consensus statements emphasize the importance of a standardized approach.[8]

    The guidelines suggest caution with opioid dose escalation and discontinuation if treatment goals are not met. However, clinical judgment and compromise may come into play for patients who have complex problems.

    In the case of chronic pain, functional restoration is a major goal of treatment. If opioids are chosen, particularly for refractory pain, tolerance and dependence can interfere. Safeguards designed to minimize these must be built into the treatment plan.[7] Prolonged, high-dose opioid therapy may be neither safe nor effective. Thus, prescribing physicians must make every effort to avoid indiscriminate prescribing, particularly for patients in whom lower-dose regimens are not effective. The answer may be found in redesigning the regimen rather than simply raising the drug dose.
    The Choice of Agents

    Despite the historical reluctance to prescribe opioids, deciding to use them has become more common in recent years for many clinicians. However, selecting the correct opioid and formulation often represents a difficult problem.

    A large variety of choices allow immediate, controlled, or rapid-release formulations in multiple dosage forms, and each drug has a unique pharmacokinetic and pharmacodynamic profile. Extraneous factors, such as the patient's previous response to opioids, rapid transit bowel syndromes, swallowing capability, compliance, and the ability to afford the medication, also must be considered. Both hydrophilic (morphine, oxycodone, hydromorphone, levorphanol, naloxone, and methadone) and lipophilic (fentanyl and buprenorphine) opioids have similar adverse side-effect potentials, especially in the opioid-naive patient, but lipophilic ones tend to produce about 30% less constipation and cognitive decline because of their rapid passage into and out of body tissues.

    Reading the Signals

    Understanding the body's response to a painful stimulus will allow a mechanistic approach to better pain control. The knowledge of how and where pharmacologic agents work allows us to choose the best treatment options for safety, efficacy, and tolerability.

    The central nervous system oversees a system of survival that signals pain, pleasure, danger, and comfort, among other things, and readies a response. This signaling system uses sensors in our skin that recognize weight, temperature, vibration, wet/dry, smooth/rough, sharp/dull, size, pressure, tickle/pleasure/pain, and movement. The system then translates, or transduces, that input so this signal can be transported across the nervous system to the brain. All along the transmission route, the signals can be altered by electrochemical means to modulate the message of sensation, either to amplify it or diminish it.

    Perhaps the most significant areas for modulation are at the junction of the peripheral and central nervous systems, at the dorsal horn, and in the ascending and descending tracts to and from the brain (Figure 2). Most of our pain medicines work in these areas to add inhibition or limit amplification. The brain then receives this input, analyzes it against previous experience, and responds to the stimulus. We call this perception.

    Figure 2. The physiology of pain.

    Regardless of the nociceptor or location of damage in the peripheral or central nervous system, a chemical soup bathes the neurons and pathways of our nervous system. Inflammation plays a continuous role in the pain process via cascades of arachadonic acid and prostaglandin release that ultimately lead to resolution of the pain response or to neuronal sensitization.[14,15]

    Rodent studies have demonstrated receptors in the area of the dorsal root ganglion that can either amplify or reduce the nociceptive signal.[16] Many of the nonopioid drugs that assist in pain control work at this site to further prevent sensitization and the loss of controlling inhibition.

    Animal studies have also furthered our knowledge of the pain transmission system and how the body modifies the nociceptive signal.[12] First, the impulses enter via distinct lamina, which appear to be directed by intensity as well as receptor type. The known receptors include 5HT-2; 5HT-3; GABAa; GABAb; NK-1; alpha-2; and delta, kappa, and mu and their subtypes. The net effect of stimulating inhibitors of these receptors is to dampen nociceptive input and prevent signal amplification. Additional chemicals bathe the afferent transmission during their ascent to the brain tissue.
    And Following the Pathways

    Specific pathways, identified as monoamine circuits, have been identified in the cerebellum, brainstem, and cerebrum.[12] These pathways correlate with the symptoms and comorbidities of major depressive disorder.[17] The chemical mediators in these pathways include serotonin, norepinephrine, dopamine, histamine, acetylcholine, and others.

    The mechanistic approach to pain management seeks to understand which pathways are involved in the perpetuation of the pain signal. Woolf[16] described 4 distinct types of pain (nociceptive, inflammatory, neuropathic, and functional) and proposed a rational approach to choosing which treatments address the unique characteristics of each. Although he considered several pharmacologic options, Wolff[16] emphasizes that mu-opioid receptor activation offers the most significant inhibition of the pain signal irrespective of etiology.

    By the time the brain becomes aware of the stimulus, the nociceptive signal has been modified; nonetheless, a reaction will occur and a response will descend toward the cord to complete the transmission loop. The body will modify the transmission by a chemical bath that can be controlled by altering and augmenting the chemical mix. Serotonin, norepinephrine, alpha-2, and opioid receptors can be stimulated to positively modify the brain's response.

    As a specific example, all antidepressants contain increasing serotonin and many also include norepinephrine.[12] It does appear that although controlling depression generally will improve comfort, elevating norepinephrine levels as well provides much better chronic pain relief. Patients with fibromyalgia appear to have an imbalance in the serotonin-norepinephrine equilibrium, with a relative elevation in norepinephrine caused by a decrease in serotonin.[13] In small studies, the serotonin and norepinephrine reuptake inhibitors (SNRIs) improved symptoms better than selective serotonin reuptake inhibitors (SSRIs) alone.[18,19]

    A major benefit observed with SNRIs and SSRIs is the reduction of fatigue, which these medicines produce as well as just treating depression.[18] Thus, the overall relief is not just reducing the amount of pain, but also improving the quality of life by enhancing mood, physical activity, and socialization.

    The Painful Personality

    Memory is inherent in the phenomenon of pain transmission. Just as it is common to associate a certain sensation with pleasant feelings, one can also associate other memories with fear, anxiety, or pain. The childhood lesson that putting a hand in fire not only hurts but also harms is ingrained in all of us. Yet, it becomes a burden to those whose pain source cannot be discovered. These continuing stimuli force the brain to revise its response, and multiple comorbidities develop to create the personality we associate with people who suffer chronic pain.

    Chronic pain is associated with significant changes to the nervous system because continued signaling of pain alters the pathways. This has an ultimate effect on the entire system, affecting its functioning. It may result in continued discomfort, even after the root cause has healed; increased neuronal sensitivity; and diminished mood, less pleasure, impaired physical and mental performance, low energy, and poor sleep. The Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria[20] to diagnose major depressive disorder require that the patient experience diminished mood, interest, and pleasure along with at least 4 of the following:

    * Hypersomnia/insomnia;
    * Psychomotor agitation/retardation;
    * Decreased energy/fatigue;
    * Inappropriate guilt/worthlessness; and
    * Decreased cognition.

    This crossover between depression comorbidities and the suffering associated with chronic pain syndromes is more than coincidental and reflects the neuroanatomy of common pathways and neurotransmitters being used to transport messages to and from the brain.[21] Medications that affect 1 diagnosis may affect the other by this mechanism and afford knowledgeable clinicians the opportunity, by appropriate prescribing, to help the patient achieve a state of balanced analgesia synergy.
    The Patient's Story

    Listening to the patient's story is a key component of evaluating a patient with chronic pain. If the clinician fails to listen to how the pain interferes with the patient's day-to-day function, treatment is likely to be ineffective. Moreover, the patient is likely to seek other care, including over-the-counter medications ( such as traditional analgesics to herbal supplements). Some 175 million people in the United States take such drugs daily and, importantly, they often don't think to tell their doctors because of the mistaken belief that these medications are benign.[22] Unfortunately, this practice increases the risk of drug interactions. For example, the combination of St John's Wort, an herbal medicine used for mild depression, and paroxitine have been reported to cause a serotonin syndrome leading to death.[22] Excess sedation from valerian root and kava kava, herbs used for anxiolysis, have also been reported, especially when the patient is also being treated with prescription or over-the-counter sedative medications.[22] There are more than 16,000 deaths from over-the-counter medication-related gastrointestinal bleeding yearly in the United States as well as great numbers of hospitalizations due to gastritis from the same cause.[22,23]

    Physiologic Consequences of Acute Pain

    Listening to patients has changed the clinical understanding of pain. The traditional concepts of benign and malignant pain did not consider the multiple effects of pain on the whole person. Now we also understand that the physiologic consequences of acute pain can lead to a systemic downward spiral starting with a general stress response. Neuroendocrine, cardiac, respiratory, gastrointestinal, urinary, musculoskeletal, and immune systems all respond in a fashion that weakens the body and impairs the recovery process.[24,25]

    The neuroendocrine response includes a decrease in insulin release and an increase in corticotropin cortisol, interleukin-1, and catecholamine levels. The clinical effect results in shifts in electrolyte balance, including sodium retention, that appear clinically as fluid retention and elevations in blood pressure.[26,27]

    Other cardiovascular changes include tachycardia, increased cardiac output, and increased vascular resistance with potential ischemia. This augments the likelihood of angina and the risk of myocardial infarction.[27,28] Pulmonary complications result directly from tightening of chest-wall muscles in response to the pain stimulus and indirectly from impaired lung excursion. Cough suppression from muscle splinting creates an environment for atelectatic changes, pneumonia, and further hypoxemia.[27]

    The catecholamine surge also affects the excretory system with decreased motility and increased bowel and bladder sphincter tone, resulting in retention, distention, elevated risk for infection, and further discomfort.[27,29]

    Muscles also can be adversely affected, with increased tone at rest, atrophy from disuse, and loss of endurance. These changes limit the very activities that can help reverse this process.[29]

    The Psychology of Suffering

    The psychologic effects of anxiety add to the problem by adversely affecting sleep and furthering the stress response. This may culminate in a depressed state if allowed to fester, and the trio of sleep deprivation, anxiety, and depression will amplify the pain sensation and intensify the suffering.[29]

    Of interest 80% of chronic pain patients and 86% of those with fibromyalgia are sleep-deprived,[27,30] which adds to the impression that their pain is worse than it actually is. This difference between the "reality" of the fibromyalgia pain and the perception of it constitutes the "suffering" that often drives the patient to seek help -- and almost as often sends them on a prolonged "doctor shopping" trip seeking real relief.

    When one considers suffering, one certainly should consider both antidepressants and psychotropic medications as mentioned previously, but at the same time, it is useful to acknowledge that opioids can provide some anxiolysis and relief at the level of the nociceptive signal as well. Nonetheless, clinicians should recognize that when pain behaviors are a part of the problem, the solution will probably require cognitive rehabilitation, which should be introduced to complete the pain management program in a comprehensive fashion that will allow patients to achieve the functional restoration they seek.

    The Traditional Paradigm

    Effective pain management also requires attention to the pain response, which changes as the continued stimulation of nociceptors lowers their threshold, creating excitation and sensitized states.[29]

    For example, pain exerts physiologic effects on the body that can be measured, as has been reported in several studies. In a trial of 50 patients with sudden onset of severe pain, investigators followed certain physiologic parameters in those whose pain was aggressively treated with opioids for 3 months and compared the results with similar patients who received inadequate pain control.[25] Hypertension, tachycardia, serum cholesterol, pregnenolone, and erythrocyte sedimentation rates were measured (Table ). The total effect of this continual stress resulted in greater fatigue from poor energy utilization and sleep impairment.
    Table. Physiologic Effects of Pain[25]
    Pain Poorly Controlled (%) Well Controlled (%)
    Hypertension, blood pressure > 140/90 56 14
    Tachycardia, heart rate > 84 42 18
    Serum cortisol elevation 14 1
    Serum pregnenolone reduction 36 3
    Erythrocyte sedimentation rate elevation 20 6

    The goal of traditional opioid-based pain management is to provide a long-lasting medication that will control pain and obviate the need for breakthrough treatments. When breakthrough pain occurs, the standard approach involves raising the baseline dose to relieve these higher pain levels. Unfortunately, higher routine doses can lead to greater adverse side effects, such as constipation, fatigue, and mental status changes.

    There is, however, a remedy for the adverse effects of a higher-baseline protocol, but this remedy requires us to rethink our basic training in pain management.

    This basic approach conforms to the old paradigm: (1) estimate the dose requirement with short-acting medications; (2) convert this to the lowest possible dose of a longer-acting medication; and (3) add 5% to 15% of that dose to cover breakthrough pain.

    This is the classic pain management paradigm we have all been taught. However, in the era of evidence-based medicine, surprisingly little evidence supports this paradigm. For example, raising the baseline dose was rooted in an erroneous concept that pain is maintained at a fairly constant rate throughout the day. Yet studies at cancer hospitals would suggest otherwise. A multicenter review revealed that breakthrough pain actually occurred 50% to 90% of the time.[18,31-33]

    Again, one needs to determine both the baseline pain need and choose the lowest effective controlled-release dose. At that point, one needs to consider breakthrough pain. Ask these questions:

    * How often does breakthrough pain occur?
    * What is its frequency?
    * What is its intensity?

    Timing of Pain Dictates Timing of Treatment

    After considering those questions, consider this: Does it make sense to give patients who experience breakthrough pain higher medication doses for 24 hours a day, when what they need is medication to cover pain spikes 4 or 5 times a day? Fortunately, the arrival of new medications provides enough choices so that one can tailor the treatment to the specific pain history of the patient.

    For example, although a long-acting opioid can provide relief for breakthrough pain in theory, it is often not the correct choice in reality because the pain episode may already be resolving when the medication starts to work. Thus, a long-acting opioid may be a poor choice for those with breakthrough pain episodes.

    The ideal drug for breakthrough pain should be fast-acting and designed specifically for breakthrough pain. Unfortunately, the ideal does not yet exist. However, some rapid-onset medications do exist that can be a good alternative choice. Oral transmucosal fentanyl, for example, typically delivers pain relief within 5-10 minutes.[34,35]

    Remember, although breakthrough pain is often linked to activity, particularly in the setting of musculoskeletal pain, end-of-dose failure can be missed as a cause of the pain. Long-acting formulations used according to manufacturers' recommended dosing schedules have been found to be involved in this cause of pain more than 70% of the time.[36] Choosing the breakthrough pain dose was predicted to be 10% to 15% of the total daily opioid dose, but again this has not held up to the microscope of scientific trials. In evaluations of more than 1000 patients, there was no correlation between the doses of opioids needed to control breakthrough pain and the total daily opioid dose.[34]

    The New Paradigm

    The new paradigm focuses on maintaining the lowest dose of baseline medications to control pain at rest combined with rapid-acting breakthrough medicines to cover the breakthrough pain episodes.

    The new paradigm possesses a 3-fold rationale. First, it is based on the availability of rapid-acting oral transmucosal medications that have an onset within minutes. Second, it builds on accepted views that opioid rotation is beneficial by reducing adverse side effects resulting from chronic use of long-acting opioids. Finally, it recognizes that episodes of breakthrough pain may be confused with end-of-dose failure from varying blood levels produced by sustained-release preparations.[37,38] The variability in blood levels resulting from various formulations of sustained-release opioids creates the scenario of breakthrough pain resulting from this inconsistency, and can lead to overdosing in an effort to regain control. Studies of controlled-release products, although requiring less frequent dosing, have failed to demonstrate better pain control than those achieved with short-acting products.[39-41]

    Thus, the advantages of sustained-release opioids include a reduced dosing schedule, the potential for sustained plasma levels, and improved compliance. The disadvantages of these compounds include inconsistent release and absorption, potential systemic effects, and the continued occurrence of breakthrough pain with the need for additional short-acting medications by 50% to 90% of patients.[42-44] The use of escalating opioid doses beyond certain values has not been studied but may be associated with neuroendocrine and neurobiological changes in the body.
    The New Paradigm in Cases of Musculoskeletal Pain

    The significance of musculoskeletal pain is that the baseline pain may be low enough that the person does not even require an opioid for pain relief. Nonetheless, that same patient often experiences activity-generated pain that is quite high. For example, a typical example of low back pain is the patient who does not experience any significant resting pain but when he or she begins an activity, the pain flares up.

    With traditional oral opioid medications, the agent must be digested and metabolized before it enters the bloodstream and finally crosses the blood-brain barrier. At that point, it finally provides pain relief. All these steps are required with hydrophilic medications, including virtually all of the opioids, except fentanyl.
    When Fast Is Better

    In this scenario, it is hardly surprising that a drug with faster transit is attractive. Some liquid opioid preparations are formulated to dissolve under the tongue, thus providing the same fast relief seen with nitroglycerin. Studies suggest that this is not the case, however, because these liquid opioid preparations do not dissolve well under the tongue.[22,45] As a result, these supposedly rapid-transit formulations actually take longer to get to brain than if they were simply swallowed like a pill or capsule.

    A better option may be fentanyl in a transmucosal form, absorbed through the mucous membranes (bypassing the stomach) directly into the bloodstream and directly into the brain, because it is lipophilic. This delivery system makes a significant difference in terms of time of onset; less than 10 minutes brings relief.[45-47] Stroke specialists often point out that "time is brain," and in a similar sense "time is pain relief."

    This approach -- this new paradigm -- helps break the cycle of uncontrolled pain. Moreover, it does not matter where patients enter the cycle, because pain feeds on itself: Pain creates avoidance behaviors, which decrease mobility, that alter the functional status and that diminish the ability to go out and participate in those activities again. The result is the classic pain patient who usually does not want to go out and does not want to be active for fear that it will increase the pain. However, this homebound state creates more pain, psychologic as well as physical pain. When the patient is eventually prodded or nagged into activity, muscle pain from stretching unused, shortened muscles is often the result.

    These are the steps in the new opioid treatment paradigm:

    * Determine the patient's baseline pain management needs;
    * Choose the lowest effective dose of a controlled-release formulation;
    * Assess the frequency, intensity, and timing of breakthrough pain; and
    * Use rapid-acting opioid medication to cover breakthrough pain.

    The case described earlier is a good example of a patient who would benefit from rapid-onset, short-acting pain relief so that she can remain active, without waiting for an oral opioid to take effect. In a study of 100 patients with non-cancer-related pain, 90% chose to continue oral transmucosal fentanyl rather than returning to their former breakthrough pain medication.[48] Most took less total medication than they had before using the transmucosal formulation, and most experienced better pain relief.


    Effective pain management requires complete and careful history -- including specific attention to possible comorbidities, such as depression, fatigue, insomnia, hypertension, and tachycardia. Moreover, effective pain management relies on careful selection of pain medications as well as an integrated approach to managing pain behaviors.

    It is especially important to monitor patients' use of over-the-counter and alternative therapies for pain to avoid potential drug-drug interactions.

    Finally, breakthrough pain is a frequent problem, but effective management of breakthrough pain requires tailored therapy that targets the timing and frequency of the breakthrough incidents and treats that breakthrough pain with fast-acting, but appropriate dosing.


    1. DeAngelis CD. Pain management. JAMA. 2003;290:2480-2481. Abstract
    2. Wolff CJ. Pain: moving from symptom control toward mechanism-specific pharmacologic management. Ann Intern Med. 2004;140:441-451. Abstract
    3. Jovey RD. Use of opioid analgesics for the treatment of chronic noncancer pain: a consensus statement and guidelines from the Canadian Pain Society, 2002. Pain Res Manage. 2003;8:3A-14A.
    4. Verbunt JA, Seelen HA, Vlaeyen JW, et al. Fear of injury and physical deconditioning in patients with chronic low back pain. Arch Phys Med Rehabil. 2003;84:1227-1232. Abstract
    5. Morike K, Platten HP, Mikus G, Klotz U. Variability in the frequency of cytochrome P450-2D6 (CYP2D6) deficiency. Br J Clin Pharmacol. 1998;46:87.
    6. Meldrum M. A capsule history of pain management. JAMA. 2003;290:2450-2455.
    7. Ballantyne JC. Chronic pain following treatment for cancer: the role of opioids. Oncologist. 2003;8567-575.
    8. Ballantyne JC. Opioid therapy for chronic pain. N Engl J Med. 2003;349:1943-1953. Abstract
    9. Portenoy RK, Foley KM. Chronic use of opioid analgesics in non-malignant pain: report of 38 cases. Pain. 1986;25:171-186. Abstract
    10. McQuay H. Opioids in pain management. Lancet. 1999;353:2229-2232. Abstract
    11. Turk DC, Brody MC, Okifuji EA. Physicians' attitudes and practices regarding the long-term prescribing of opioids for noncancer pain. Pain. 1994;59:201-208. Abstract
    12. Hyman SE, Cassem SH. Scientific American Medicine III, subsection XIX, Chapter 11, 1996.
    13. Goldenberg D, Mayskiy M, Mossey C, et al. A randomized cross over trial of fluoxitine and amitripyiline in the treatment of fibromyalgia. Arthritis Rheum. 1996;39:1852-1859. Abstract
    14. Baba H, Kohno T, Moore KA, Woolf CJ. Direct activation of rat spinal dorsal horn neurons by prostaglandin E2. J Neurosci. 2001;21:1750-1756. Abstract
    15. Delfs JM, Zhu Y, Druhan JP, Aston-Jones G. Noradrenaline in the ventral forebrain is critical for opiate withdrawal-induced aversion. Nature. 2000;410:430-431.
    16. Woolf CJ. Pain: moving from symptom control toward mechanism-specific pharmacologic management. Ann Intern Med. 2004;140:441-451. Abstract
    17. Stahl SM, Zhang L, Damatarca C, Grady M. Brain circuits determine destiny in depression: a novel approach to the psychopharmacology of wakefulness, fatigue, and executive dysfunction in major depressive disorder. J Clin Psychiatry. 2003;64(suppl14):6-17.
    18. Wolfe F, Cathey MA, Hawley DJ. A double blind placebo controlled study of fluoxitine in fibromyalgia. Scand J Rheumatol. 1994;23:255-259. Abstract
    19. Portenoy RK. Symposium on breakthrough pain. Program and abstracts of the 15th Annual Scientific Meeting of the American Pain Society; November 14-17, 1996; Washington, DC.
    20. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV). Washington, DC: American Psychiatric Association; 1994.
    21. Stahl SM, Shayegan DK. The psychopharmacology of ziprasidone: receptor-binding properties and real-world psychiatric practice. J Clin Psychiatry. 2003;64(suppl14):6-17.
    22. Reuters Health 14:39:21 1/30/03/Harris poll. OTC Pain Meds: What Helps What Hurts. Available at Accessed May 24, 2004.
    23. Singh G, Triadafilopoulos G. Epidemiology of NSAID induced gastrointestinal complications. J Rheumatol. 1999;26(suppl56):18-24.
    24. Bonica JJ. Biologic markers can even be followed in severe intractable pain including hypertension, tachycarida, serum cortisol, serum pregnenolone and sedimentation rate. In: Ashburn MA, Rice LJ, eds.The Management of Pain, Vol. 1, 2nd ed. New York, NY: Churchill Livingstone; 1990.
    25. Tennant F, et al. Physiologic abnormalities as biologic markers in severe intractable pain. Program and abstracts of the 25th Annual Meeting of the American Pain Society; March 20-23, 2003; Chicago, Illinois.
    26. Kehlet H. Effect of pain relief on the surgical stress response. Reg Anesth.1996;21:35-37.
    27. Cousins M, Power I. In: Wall PD, Melzack R, eds. Textbook of Pain. 4th ed. New York, NY: Churchill Livingstone; 1999:445-491.
    28. Bowler DB, et al. In: Cousins MJ, Phillips GD, eds. Acute Pain Management. 1986:187-236.
    29. Nimmo WS. Effect of anaesthesia on gastric motility and emptying. Br J Anaesth. 1984;56:29-37. Abstract
    30. Kennedy M, Felson DT. A prospective long-term study of fibromyalgia syndrome. Arthritis Rheum. 1996;39:682-685. Abstract
    31. Caraceni A, Portenoy RK. An international survey of cancer pain characteristics and syndromes. IASP Task Force on Cancer Pain. International Association for the Study of Pain. Pain. 1999;82:263-274. Abstract
    32. Fine PG, Busch MA. Characterization of breakthrough pain by hospice patients and their caregivers. J Pain Symptom Manage. 1998;16:179-183. Abstract
    33. Zeppetella G, O'Doherty CA, Collins S. Prevalence and characteristics of breakthrough pain in cancer patients admitted to a hospice. J Pain Symptom Manage. 2000;20:87-92. Abstract
    34. Adams D, et al. J Pain. 2003;3(suppl1):49. Abstract 794.
    35. Lichtor JL, Sevarino FB, Joshi GP, et al. The relative potency of oral transmucosal fentanyl citrate compared with intravenous morphine in the treatment of moderate to severe postoperative pain. Anesth Analg. 1999;89:732-738. Abstract
    36. Multicenter, Dose Titration Studies of Oral Transmucosal Fentanyl Citrate (OTFC) for the Treatment of Breakthrough Pain in Cancer Patients Taking Stable Doses of Oral Morphine and Transdermal Fentanyl, data on file at Cephalon, Inc.
    37. Nicholson B. Sustained Release Opioids: New Directions in Chronic Pain. London, England: Journal of the Royal Society of Medicine Press.
    38. Portenoy RK. Opioid therapy for chronic non malignant pain: a review of the critical issues. J Pain Symptom Manage. 1996;11:203-217. Abstract
    39. Adams D, et al. Variability of blood levels with SR opioids. J Pain. 2002;49(suppl3). Abstract 794.
    40. Hale ME, Fleischmann R, Salzman R, et al. Efficacy and safety of controlled-release versus immediate-release oxycodone: randomized, double-blind evaluation in patients with chronic back pain. Clin J Pain. 1999;15:179-183. Abstract
    41. Parris WC, Johnson BW Jr, Croghan MK, et al. The use of controlled-release oxycodone for the treatment of chronic cancer pain: a randomized, double-blind study. J Pain Symptom Manage. 1998;16:205-211. Abstract
    42. Stambaugh JE, Reder RF, Stambaugh MD, et al. Double-blind, randomized comparison of the analgesic and pharmacokinetic profiles of controlled- and immediate-release oral oxycodone in cancer pain patients. J Clin Pharmacol. 2001;41:500-506. Abstract
    43. Nicholson, B. Sustained-Release Opioids New Directions in Chronic Pain. London, England: Journal of the Royal Society of Medicine Press.
    44. Bourget P, Lesne-Hulin A, Quinquis-Desmaris V. Study of the bioequivalence of two controlled-release formulations of morphine. Int J Clin Pharmacol Ther. 1995;33:588-594. Abstract
    45. Grond S, Radbruch L, Lehmann KA. Clinical pharmacokinetics of transdermal opioids: focus on transdermal fentanyl. Clin Pharmacokinet. 2000;38:59-89. Abstract
    46. Mystakidou K, Befon S, Tsilika E, et al. Use of TTS fentanyl as a single opioid for cancer pain relief: a safety and efficacy clinical trial in patients naive to mild or strong opioids. Oncology. 2002;62:9-16. Abstract
    47. Gourlay GK. Treatment of cancer pain with transdermal fentanyl. Lancet Oncol. 2001;2:165-172. Abstract
    48. Tennant F, Herman L, Reinking JC, Snyder N. The use of oral transmucosal fentanyl citrate for breakthrough pain in severe, non-malignant chronic pain. J Pain Symptom Manage. 2002;12:130-135.

    Authors and Disclosures
    As an organization accredited by the ACCME, Medscape requires authors and editors to disclose any significant financial relationship during the past 12 months with the manufacturer of any product that may relate to the subject matter of the educational activity, whether or not the activity is commercially supported. Authors are also asked to disclose any mention of investigational products or unapproved uses of products regulated by the U.S. Food and Drug Administration.


    Steven Simon, MD, RPh
    Assistant Clinical Professor, Department of Physical Rehabilitation and Medicine, The University of Kansas, Lawrence; Assistant Clinical Professor, Department of Family Practice, The University of Health Sciences, Kansas City, Missouri; Medical Director, Rehabilitation Services, Shawnee Mission Medical Center, Mission, Kansas

    Disclosure: Steven Simon, MD, RPh, has received grants for studies from Allergan, Endo, Pfizer, and Daiichi. He has served as a speaker for Pfizer, Merck, Alpharma, Ortho-McNeil, and Cephalon. Dr. Simon has reported that he does not discuss any investigational or unlabeled uses of commercial products in this activity.

    Clinical Editors

    Priscilla Scherer, RN
    Contributing Site Editor, Medscape

    Disclosure: Priscilla Scherer has no significant financial interests or relationships to disclose.

    Scott M. Williams
    Clinical Editor, Medscape HIV/AIDS

    Disclosure: Scott Williams has no significant financial interests to disclose.

    Registration for CME credit, the post test and the evaluation must be completed online.
    To access the activity Post Test and Evaluation link, please go to: