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The International Association for the Study of Pain defines pain as "an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage." (1) Acute pain usually resolves once the underlying cause and symptoms have been treated. Chronic pain, on the other hand, persists beyond the point of tissue healing, typically for at least 3 to 6 months, even when there is no evidence of tissue damage (Table 1). (2)

The prevalence of chronic pain is high, and its impact on individuals and society is profound. More than one quarter of US adults (approximately 76 million) are estimated to suffer from chronic noncancer pain, almost twice as nanny people as those with diabetes, heart disease, stroke, and cancer combined. A majority of adult responders to the National Health and Nutrition Examination Survey (NHANES) for the years 1999 to 2002 reported having pain that lasted a year or longer (Figure 1). (3) This pain may take any of several forms and be located in any of several areas. In the NHANES, 10% of respondents reported back pain; leg or foot pain was reported by 7%; and 4% each reported pain in their heads or their arms and hands. (4) Chronic diseases and conditions associated with pain include osteoarthritis, fibromyalgia, migraine, sickle cell disease, phantom limb pain, complex regional pain syndrome, postherpetic neuralgin, and peripheral neuropathy. (5) Because chronic pain is so pervasive, clinicians in every branch of medicine need to address its recognition and treatment.

Chronic noncancer pain can have profound effects on patients' lives and livelihoods (Table 2), (5-6) with costs for patients, their families, and society as a whole. (5) The annual direct fiscal cost in the United States has been estimated to be approximately $100 billion. (7) In addition to direct costs, such as those for physician visits and medications, there are indirect costs of chronic pain that include those of lost productive time. Results of a study of almost 29,000 US workers indicated that approximately 13% of the workforce loses productivity because of pain, and this loss translates to a cost of more than $61 billion annually. (8)

Recently, a multidisciplinary panel of 21 thought leaders in pain medicine, palliative care, anesthesiology, and other related fields was convened by the American Pain Society (APS) and the American Academy of Pain Medicine (AAPM). This panel was charged with reviewing the available evidence and formulating an updated set of clinical guidelines for the long-term use of opioid therapy in the treatment of chronic noncancer pain. (9) hi Septembcr 2009, the symposium, "Practical Perspectives for the Frontline Clinician," was held to review the 2009 APS/AAPM guidelines, discuss the current treatmcnt options for chronic noncancer pain, and facilitate the safe long-term use of opioid therapy for treating chronic pain. This supplement summarizes the information presented during the symposium.

The pain pathway consists of ascending and descending components, along which distinct processes occur (Figure 2). (10) The fibers along which sensory signals are carried are A[beta] fibers (large-diameter, myelinated fibers that primarily respond to light touch or vibration), A[delta] fibers (small-diameter, myelinated, rapid-conduction fibers), or C fibers (unmyelinated, slow-conduction fibers). Nociceptors are the free endings of primary afferent nerve fibers that are sensitive to noxious stimuli (thermal, mechanical, or chemical). The A[delta] and C fibers are involved in nociception, the process by which these sensory receptors convey information regarding tissue damage to the central nervous system. This can occur when any tissue, organ, or nerve is injured. (2,5)

A cascade of events is set in motion by injury. The release of pain-generating substances and mediators of inflammation causes nociceptors to become hypersensitive to noxious stimuli. Nociception comprises four steps: transduction, transmission, modulation, and perception. (2)

* Transduction: This is the phase at which afferent nerve endings translate the energy from noxious stimuli into nociceptive impulses.

* Transmission: During this stage, the nociceptive impulses are conveyed from the peripheral site of injury to the dorsal horn of the spinal cord and from there to the brain.

* Modulation: This is the process by which the nociceptive impulses are either inhibited or amplified, with input from both the ascending and descending pathways.

* Perception: This is the subjective feeling of pain, influenced by the interaction of the prior three steps and the patient's psychological input.

Pain Is a Multidimensional Experience

As mentioned, psychological factors affect the way an individual experiences pain. In 1965, Melzack and Wall (11) introduced the gate control theory of pain modulation, which postulated the existence of a gate in the dorsal horn that is triggered to act by signals from the ascending and descending pain pathways, as well as by input from the brain. When these combined effects cause the gate to be open, pain is perceived as more intense (eg, when an individual is alone at night), whereas, when the gate is closed, pain is felt less intensely (eg, when an individual is distracted by the company of other people). (2,11)


Melzack (11) went on to develop a more complex model of pain modulation that expanded the role of neuropsychological input to one that could exert an influence independent of that of the body. The factors contributing to this "body-self neuromatrix" include genetic disposition as well as the impact of psychological stress and early experience (Figure 3). (11) An example of the latter is the finding that boys who were circumcised without anesthetic, those who were circumcised with anesthetic, and those who were not circumcised at all react differently to normally painful input later in life. (12) Thus, "pain is a multidimensional experience produced by multiple influences." (11)

Pain may be classified into three categories: nociceptive, inflammatory, and neuropathic. Nociceptive pain, or normal pain, is the sensation resulting directly from a noxious stimulus (eg, an accidental cut or burn or a surgical incision) and fades once the stimulus is removed. According to a written communication from Gilbert J. Fanciullo, MD, MS (September 2009), nociception is "the strict wiring portion of the neuromatrix experience of pain." Inflammatory pain results from tissue injury followed by an inflammatory reaction that involves the release of "algogenic" substances that cause sensitization. In the setting of inflammation, otherwise "silent" nociceptors also may be activated and may generate further pain. Except in the case of ongoing inflammation, such as that with rheumatoid arthritis, this pain also resolves after the tissue heals. Neuropathic pain is the result of injury to nerves or to sensory transmission systems. It is thought that neuropathic pain is caused by more than one mechanism. (2,13)


Pain can also be categorized temporally, as illustrated in Figure 4 on page 6. When peripheral nociceptors are stimulated, the pain is initially transmitted by A[delta] fibers. This "first pain" is a sharp, pricking sensation that is well localized and of brief duration. "Second pain" which is transmitted by C fibers, is more of a burning or aching pain that lasts longer than does first pain and is more diffuse and visceral. (14-15)

Once the immediate unpleasant sensation of pain is controlled, the primary goal in the treatment of acute pain is to prevent its evolution to chronic pain, which is more difficult to manage. Unrelieved inflammatory or neuropathic pain can lead to a transition from peripheral to central sensitization, which results from excessive, persistent nociceptive signals bombarding the central nervous system. As the nociceptive signals persist, glutamate is released, activating the N-methyl-D-aspartate (NMDA) receptors, which are involved in the perpetuation of chronic pain. These long-term neuroplastic changes result in conditions such as allodynia (a pain response to a normally innocuous stimulus) and hyperalgesia (exaggerated and/or prolonged response to a moderately noxious stimulus), as well as a reduction in opioid effects. (2,16-17) Because these chronic pain signals can become embedded in the spinal cord and function in the absence of any noxious stimulus, timely, aggressive treatment to prevent the transition from acute to chronic pain is of utmost importance.

Preemptive Analgesia

Another source of chronic pain, in addition to disease and accidental injury, is iatrogenic in origin. Surgery can be thought of as a "planned injury," (18) and chronic pain can develop following surgical procedures as easily as following accidental injury if sufficient pain control is not used. Persistent postsurgical pain, lasting more than 3 to 6 months after surgery, has been documented in patients undergoing common surgical procedures as follows: (13)

* Amputation: 30% to 50%

* Coronary artery bypass surgery: 30% to 50%

* Thoracotomy: 30% to 40%

* Breast surgery (lumpectomy or mastectomy): 20% to 30%

* Caesarean section: 10%

* Inguinal hernia repair: 10%.

The concept of preemptive analgesia proposes that analgesia be initiated before application of the noxious stimulus to break the pattern of evolution from acute to chronic pain. Because the timing of surgery is known beforehand in most cases, this context presents an almost ideal setting for the planning of preemptive analgesia. (12) Using knowledge of the patient's history and the nature of the surgery, the clinician can plan a preemptive regimen that uses one type or several types of analgesia at one point or several points along the pain pathway to prevent both peripheral and central sensitization. (15) As this technique is honed and used more frequently, perhaps the incidence of chronic postsurgical pain will decrease.


Importance of Clinical Practice Guidelines

In clinical practice, especially in the context of treating chronic pain, there is a wealth of anecdotal information and opinions, but there is a dearth of high-quality evidence supporting any clear treatment strategy. Clinicians caring for patients with chronic pain face multiple, often complex etiologies; varying degrees of disability and discomfort; and a diversity of issues, ranging from how to achieve adequate relief for patients in pain to minimizing the risks of addiction, misuse, and diversion of controlled substances, as well as how to overcome barriers to adequate treatment. A substantial proportion of the published evidence is (1) narrow in scope, looking at one issue but not addressing associated problems; (2) inconclusive, failing to provide unequivocal answers to clinical questions; or (3) heterogeneous, with separate groups developing their own criteria for studies that cannot later be pooled to yield overall answers. Thus, there continue to be gaps between evidence and practice and substantial variations in practice.

The Institute of Medicine defines clinical practice guidelines as "systematically developed statements to assist practitioner and patient decisions about appropriate health care for specific clinical circumstanccs" (19) In contrast to systematic reviews, clinical practice guidelines are written with the goal of providing concrete advice for clinicians and their patients to use in formulating treatment plans. In doing so, guideline authors try to address all the issues associated with a particular condition and the available treatments, synthesizing not only trial results, but also expert judgment and experience. The aim of the multidisciplinary panel that produced the APS/AAPM guidelines was to provide actionable items for use in the treatment of chronic pain.

Using the 2009 APS/AAPM Guidelines to Improve Patient Care

Every country where opioids are used to treat chronic pain will have guidelines, and although they all differ in some ways, the fundamental principles are the same. All guidelines recommend that treatment selection be based on a patient-assessment process that begins with a comprehensive medical history and physical examination. They all also recommend that opioid treatment, which should be introduced only after nonopioid alternatives have failed, be goal directed or at least that some measure be established to assess the effects of therapy. The guidelines all suggest that a single physician coordinate care (a "medical home") (9) and a single pharmacy be involved, whenever possible, to keep follow-up consistent. Therapy should not be initiated until the physician and patient have discussed the benefits and drawbacks of opioid therapy and the patient has demonstrated understanding of that information. Finally, all guidelines recommend regular follow-up to assess whether treatment goals are being achieved and to monitor for signs of opioid abuse.

Evidence Supporting Recommendations

The panel formulating the 2009 APS/AAPM guidelines used the criteria shown in Table 3 to grade the quality of the evidence and the strength of each recommendation. (9) A strong recommendation results from a high benefit-to-risk ratio, and a weak rating is based on a more equal ratio of benefit and risk. (9) The panel identified several research gaps, concluding that, overall, evidence is quite limited. Thus, none of the recommendations in the guidelines was supported by high-quality evidence; rather, most were prompted by unanimous (or near-unanimous) consensus among the experts on the panel. (9)

Unfortunately, the general understanding of what is meant by evidence-based medicine is not strong. David Sackett, (20) the "father" of this concept, did not intend that therapies be withheld from patients in need based on the absence of published reports of randomized, controlled trials. He defined evidence-based medicine as "the conscientious, explicit, and judicious use of current best evidence in making decisions about the care of individual patients" emphasizing that the available external evidence should be integrated with the clinician's own expertise and experience rather than replacing them. (20) Thus, the consensus recommendations of experts in the field of pain treatment yield a strong grade for therapy. (21)

Novel Aspects of the 2009 APS/AAPM Guidelines

Patient Selection/Risk Stratification

In contrast to previous guidelines, the 2009 APS/AAPM guidelines strongly recommend a clear process of risk stratification and patient selection, with acknowledgment of the fact that long-term opioid therapy is not appropriate for all patients with chronic noncancer pain. Patient selection for opioid therapy should begin with a thorough evaluation of the benefit-to-harm ratio for each individual. This involves not only a physical examination and patient history, but also assessment of the risk of opioid abuse or misuse by the patient, starting with a family history of alcohol or other drug abuse and investigation into the presence of psychiatric conditions. (9)

As illustrated in Figure 5, the prevalence of nonmedical use of pain relievers remains consistently higher than that of other prescribed and illicit drugs (including cocaine), with the exception of marijuana. (21) Recognizing current or potential opioid misuse can be difficult. Patient self-report may not be reliable, so other methods, such as urine drug screening, family member interviews, and pill counts, must be added to complete the picture.(9,22) Although urine toxicology has a potentially important place in minimizing risk, (22) the panel found only weak evidence supporting routine urine drug screening, and this recommendation (both for patients at high risk and for those not at high risk for drug-related aberrant behavior) was the only one not receiving unanimous approval. (9) Several screening instruments, some of which are described briefly in Table 4, (9,23-25) are available for use in identifying aberrant drug-related behavior.


Treatment Issues

Several issues received a great deal of attention from the panel, including the following:

* Informed Consent: When long-term opioid therapy is initiated, informed consent should be obtained from the patient. A written management plan can be helpful in managing expectations and clarifying patient and clinician responsibilities. (9)

* Dose Escalation: After extensive discussion, the panel concluded that if patients require frequent dose escalations, clinicians should evaluate the potential causes and recalculate the benefit-to-harm ratio. Although, in theory, opioids have no ceiling dosage, the panel agreed that a dosage exceeding 200 mg/day of oral morphine or its equivalent is a reasonable definition of high-dose therapy warranting more intense monitoring and consideration of changes in the regimen. (9)

* Multidisciplinary/Multimodal Pain Management: The panel found strong evidence to support an approach to pain treatment that integrates "therapies that target the psychosocial and functional factors that contribute to or are affected by [chronic noncancer pain]." The panel strongly advocates that primary clinicians coordinate with other practitioners to provide patients with interdisciplinary pain-management services. (9)

* Treating Breakthrough Pain: The evidence supporting this practice was very weak, despite its being a common practice. Breakthrough pain should be assessed to determine whether it represents disease progression or a new pain condition unrelated to the original condition. Clinicians need to weigh the benefits and risks of prescribing additional opioid medication, and they should consider use of nonopioid drugs and nonpharmacologic interventions before adding an opioid. (9)


Clinicians should monitor their patients on long-term opioid therapy at regular intervals or whenever circumstances dictate. Monitoring serves to determine whether therapeutic goals are being achieved; whether the current therapeutic regimen is remaining effective, with a sufficiently low incidence and severity of adverse events; and whether patients' risk of opioid abuse/misuse has remained sufficiently low as well. (9)

Two instruments that may be useful in assessing patients' progress are the Pain Assessment and Documentation Tool (PADT) and the Current Opioid Misuse Measure (COMM), both of which provide questions to be answered by patients. The PADT categorizes questions into four categories, commonly known as the "Four A's": Analgesia, Activities of Daily Living, Adverse Events, and Aberrant Drug-Related Behavior. (26) The COMM asks 17 questions aimed at evaluating patients' current psychological status and patterns of drug use and identifying potentially aberrant behavior. (9) Whichever instruments are used in follow-up evaluation, the most important requirement is that monitoring be performed and that, at every stage of evaluation and treatment, clinicians keep thorough records. Thorough, regular documentation can prevent misunderstandings and mishaps related to analgesic therapy, and it also provides the treating physicians with a solid tool for defense in case of litigation.

The APS/AAPM guidelines, recognizing that chronic noncancer pain is typically a complex condition, recommend that long-term opioid treatment be part of a multidisciplinary therapeutic strategy that also addresses psychological problems, functional impairment, and environmental factors. (9) The goals of treatment are reduction of pain, restoration of function, and improvement in sleep, mood, and overall quality of life. (27)

Nonpharmacologic Modalities

At the initiation of treatment, the patient and his or her family/caregivers should be provided with educational materials regarding the causes/etiologies of the pain, the reason for each recommended intervention, and the importance of improving functionality. The patient's expectations for treatment outcomes need to be managed as well, as do the family's expectations. (2,27) One study of patients with low back pain found that education alone provided almost as much benefit as did physical therapy or chiropractic manipulation. (28)

A multidisciplinary approach always includes an assessment of lifestyle habits and recommendations for appropriate modification, when necessary. For patients with chronic noncancer pain, smoking cessation is a very important change. Use of nicotine products has been associated with both increased pain and reduced effectiveness of some medications used to treat pain, such as antidepressants. Losing excess weight, avoiding moderate to excessive alcohol use, and incorporating exercise into the patient's lifestyle are also important modifications. (2,27)

Physical therapy may involve range-of-motion exercises, stretching exercises, strength training, and/or cardiovascular conditioning. Therapeutic massage and medical acupuncture also may provide benefit, in terms of promoting relaxation and reducing tension, decreasing pain, and improving sleep. Although immobilization may be helpful in the period immediately following injury, it generally is not advisable in the long term because of potential problems such as cardiovascular deconditioning and muscle atrophy. Rather, patients should be encouraged to persist with a structured therapeutic exercise program, despite possible early discouragement. There is strong evidence to support the benefits of exercise therapy for patients with certain types of chronic pain. (2,28-29) As mentioned, adjunctive psychotherapy is one of the few well-supported recommendations in the APS/AAPM guidelines. Cognitive-behavioral therapy, which is aimed at helping patients adjust their attitude toward and cope better with their chronic pain, is the most consistently effective psychotherapeutic intervention for patients with chronic pain. It encompasses coping-skills training, relaxation, and stress management, among other techniques. Relaxation training may involve meditation, biofeedback, imagery, and breathing exercises. Hypnosis, sometimes considered a "more concentrated form of relaxation," involves suggestion to the patient for pain relief and has been particularly beneficial in controlling postsurgical pain. (2,9)


Complementary and alternative medicine (CAM) comprises several diverse modalities, including some of the techniques discussed above, such as meditation. CAM also includes physical interventions such as massage, acupuncture, chiropractic manipulation, and use of transcutaneous electronic nerve stimulation (TENS). Although there have been few well-controlled studies of acupuncture, it has been observed to help relieve pain and restore mobility. The ability of chiropractic manipulation to reduce muscle tension and relieve musculoskeletal pain is supported by limited evidence as well. TENS, which stimulates An fibers to decrease nociceptive pain transmission, has been shown to improve sleep, increase activity, and reduce the need for analgesic medication in several trials of patients with chronic pain. Because the use of CAM has increased and is likely to continue increasing, it is advisable for physicians to be familiar with and maintain an open-minded attitude toward these modalities. (2,28,30)


Every stage along the pain pathway is a target for analgesic treatment (Figure 6). (5,12,15) Multimodal analgesia, also known as balanced analgesia or rational polypharmacy, has gained favor rapidly as a practical approach to the treatment of chronic pain. The principle behind this approach is the use of two or more pharmacotherapies with different mechanisms of action--or that act at different sites along the ascending and descending pain pathways--to provide additive or synergistic benefits and/or to minimize the adverse effects of either or both agents. The combination of an opioid and a nonopioid is a therapeutic tactic that can increase overall analgesia without increasing opioid dose. The issue of potential drug interactions must be addressed as part of a rational polypharmacy strategy. (5,31-32)

Nonopioid agents used in analgesia (Table 5) include acetaminophen, non-selective nonsteroidal anti-inflammatory drugs (NSAIDs), cyclooxygenase (COX)-2-selective NSAIDs, topical agents, and a group of drugs known as "adjuvant analgesics" which comprises agents primarily indicated for uses other than analgesia (such as antidepressants and antiepileptics). (2,5,7,33) The gastrointestinal (GI) side effects of nonselective NSAIDs, which prompted the development of COX-2 inhibitors, make their long-term use problematic. The COX-2 inhibitors, however, have been found to confer high cardiovascular risk, making them less-than-ideal agents for long-term use as well. (5) Topical NSAIDs (eg, diclofenac 1% gel), with minimal systemic exposure, provide efficacy for selected patients with a low rate of the cardiovascular and renal adverse effects of oral NSAIDs. (34)


Opioids can be classified by their sites and mechanisms of action. They may have receptor affinity, which indicates the strength of a drug's interaction with its receptor, and/ or efficacy, which describes the strength of effect of the binding to the receptor. The [micro]-opioid receptors are thought to mediate analgesia, euphoria (which increases the tendency toward abuse), sedation, respiratory depression, physical dependence, and GI motility; [kappa] receptors affect spinal analgesia, sedation, dysphoria, dependence, and respiratory depression. The influence of the [delta]-opioid receptors is not as well known, but they may have psychotomimetic and dysphoric effects. Most opioids are receptor agonists that stimulate the [micro]-opioid receptors in pain pathways. Some are partial agonists, with high affinity but low efficacy at the [mu] opioid receptor. (35-36)

Opioids generally activate receptors at four points in the pain pathway: (37)

* In the periphery, they inhibit the activation of nociceptors and inhibit the release of inflammatory mediators.

* At the central terminal of spinal cord C fibers, they prevent the release of pain neurotransmitters.

* On second-order afferent cells, they prevent ascending transmission of the pain signal.

* At opioid receptors in the midbrain, they "turn on" the descending systems through disinhibition.

The Drug Enforcement Administration also classifies opioids according to their potential for addiction and/or abuse. Schedule I drugs, which include heroin and marijuana, are generally not used medically and are considered to have high abuse potential. Schedule II drugs also are thought to have high abuse potential, but are used medically. This group includes morphine, oxycodone, hydromorphone, oxymorphone, meperidine, methadone, fentanyl, amphetamines, and tapentadol. Schedule III drugs, rated as having moderate abuse potential, include hydrocodone and codeine. The benzodiazepines, propoxyphene, and butorphanol are included in Schedule IV. This category is considered to have low abuse potential, as is Schedule V, which includes buprenorphine. (35)

Possible drug-drug interactions need to be considered when polypharmacy is being planned, as well as in the context of other medications that each patient may be prescribed. The majority of marketed drugs, including opioids, are metabolized by enzymes in the cytochrome P (CYP)-450 system. The CYP3A4 and CYP2D6 isoforms account for the metabolism of most opioids (Table 6) [written communication, Robert L. Barkin, PharmD, September 2009]. (32,38) The extent to which drugs are metabolized varies between patients, influenced by genetic and other factors. (31,35) Drugs that are metabolized by an isoform are substrates of that isoform. Drugs that stimulate the synthesis of an isoform (inducers) enhance its metabolizing action and can, thereby, reduce plasma levels of substrates for that isoform, whereas inhibitors compete for the binding sites of an isoform, which may reduce metabolism of a substrate and, thus, increase plasma levels of that drug.

The side effects of opioids are associated with their drug-specific binding to opioid and nonopioid receptors. The most common adverse effects of opioids are GI symptoms, specifically constipation, nausea, and vomiting. Constipation is so common that it is considered reasonable to initiate a bowel regimen (eg, increased fluid and fiber intake, use of stool softeners and/or stimulant laxatives) prophylactically for patients at risk for development of constipation, such as older patients. Tolerance to constipation does not develop with continued opioid treatment. Nausea and vomiting, on the other hand, tend to diminish with ongoing opioid use. If they do not disappear, antiemetic therapy is appropriate. Some adverse effects, such as sedation and pruritus, are dose dependent and are typically managed via dose reduction. Pruritus can be treated with an antihistamine as well. When patients are started on opioid therapy or their dosages are increased, they should be cautioned that their cognition may be affected initially. They should take particular care when using motorized vehicles and machinery and use vocational safety practices. They also should be advised of the risks of concomitant use of other sedating substances. Anticipating and managing opioid adverse effects is likely to foster adherence to therapy) (31,39-40)

Two issues of great concern to patients with chronic pain are inadequate control of their pain and its impact on their ability to sleep. In a survey of more than 600 patients with chronic pain conducted by McCarberg and colleagues, (6) 81% of patients taking short-acting pain medications reported inadequate pain control. Whereas, short-acting, immediate-release (IR) opioids cause rapid increases and decreases ill serum opioid levels, most long-acting opioids (including extended-release [ER], sustained-release, and some controlled-release formulations) tend to cause gradual increases to therapeutic levels, extended maintenance at those levels, and gradual declines. Thus, although there is a paucity of head-to-head comparison data, it seems apparent that ER formulations are more likely to provide patients with consistent pain relief" and the likelihood of uninterrupted sleep. An optimal regimen may be one that starts with an IR formulation, using this until a stable dose is achieved, and then is converted to an ER formulation of the same medication. (31,41)

Novel Agents

Descending pain-modulatory neurons release neurotransmitters in the spinal cord, particularly serotonin and norepinephrine. These two neurotransmitters directly inhibit pain-transmitter release from the incoming nociceptive signal and inhibit the second-order pain-transmission cell. (37) A novel concept in analgesia is that of single agents with dual mechanisms of action. One unique example of this concept is tapentadol, which is both a [micro]-opioid receptor agonist and a norepinephrine reuptake inhibitor. Tapentadol differs from tramadol, the other approved dual-action analgesic, in that tapentadol is a greater norepinephrine reuptake inhibitor and a very minor, nontherapeutic scrotonin reuptake inhibitor, whereas, tramadol is a strong serotonin reuptake inhibitor. In addition, tapentadol is a Schedule II opioid, whereas tramadol is not a scheduled substance. (35,38-42)

The efficacy and safety of tapentadol IR have been compared with those of oxycodone in four clinical studies--one (not placebo-controlled) with patients who had low back pain or pain from knee or hip osteoarthritis (the duration of this study was 90 days, and a subset of patients [greater than or equal to]75 years of age was analyzed), (43) one (placebo-controlled) of patients with osteoarthritis pain who were candidates for hip or knee replacement, (42) and two (both placebo-controlled) of patients with postsurgical (bunionectomy) pain. (44-45) In all of these trials, IR tapentadol demonstrated efficacy that was not inferior to that of oxycodone, and both drugs demonstrated efficacy significantly superior to that of placebo (P<0.001) when placebo was included in the comparison. (42-45)

In a study of patients' preferences for postoperative recovery, Eberhart and colleagues (46) found that the desire to avoid experiencing nausea or vomiting following surgery actually ranked higher than did patients' desire to experience no or only mild pain. Clearly, therefore, minimizing GI symptoms is important to patients and could foster adherence to opioid therapy. As illustrated in Figure 7, the incidence of GI adverse events was mostly higher with oxycodone than with IR tapentadol in all four of the trials. (42-45) In the low-back-pain/osteoarthritis study, which was designed primarily to compare the tolerability of the two drugs, patients taking either dosage of tapentadol were significantly less likely than were those taking either dosage of oxycodone to report nausea, vomiting, or constipation (P< 0.001). (43) Additionally, tapentadol causes little euphoria, and few patients experience withdrawal symptoms upon cessation of its use. (38) These characteristics are likely to result in a low potential for likeability or abuse.


An ER formulation of tapentadol is currently in phase III studies. In recently completed studies in chronic low back pain and chronic osteoarthritis knee pain, tapentadol ER provided effective pain relief. (15,47) Additionally, in these trials, a substantially larger proportion of patients taking controlled-release oxycodone experienced overall adverse events and, specifically, GI adverse events. Tapentadol ER has also been studied in moderate to severe diabetic peripheral neuropathic pain, with promising results. (48)

The high prevalence of chronic noncancer pain and the likelihood that under- or untreated acute pain will evolve into chronic pain highlight the need for clinicians to recognize the importance of treating all pain quickly and aggressively. Patients should be assessed thoroughly for the type and severity of pain that they are experiencing, comorbidities that they may have, and any medications that they are taking. They should also be assessed for their likelihood of diverting or abusing opioids and any other issues that may affect their analgesic treatment. A personalized, specific therapeutic regimen should be planned for each patient, with the risks and benefits of each treatment weighed on an individual-patient basis, and the patient's progress and status should be monitored regularly.

The therapeutic strategy most likely to be effective in managing chronic pain for the majority of patients is a multidisciplinary one, involving nonpharmacologic interventions of both a physical and a psychological nature, in addition to pharmacotherapy. Similarly, multimodal pharmacotherapy is most apt to provide maximal pain relief with minimal risk of adverse events, including opioid abuse. Opioid therapy has potential risks, but it also can be of great benefit for patients with chronic pain. When a patient is deemed a suitable candidate for opioid therapy, education is an essential component of the treatment plan, as is regular monitoring. Rational polypharmacy should be planned with attention to the possible interactions of the agents being used. New agents entering the market, with dual mechanisms of action, offer not only the possibility of greater efficacy than that of single-mechanism agents, but also a lower risk of drug interactions.

Clinical practice guidelines are meant to help clinicians and their patients make educated choices regarding treatment, avoiding the pitfalls of trying to select treatment based only on sparse published studies or personal anecdotes. They are not meant to replace clinical experience and judgment, but their use should facilitate the planning of a regimen that will control patients' pain most effectively.

Practical Perspectives for the Frontline Clinician: Long-Term Opioid Therapy in Chronic Noncancer Pain

Post-Test Questions

Complete the CME post-test questions below online at along with the evaluation form provided online. If you prefer a hard copy of the post-test and evaluation form, please call Penn State Continuing Education at 717-531-6483 or e-mail Please reference activity code G4094-10-R.

1. More than -- of US adults are estimated to suffer from chronic noncancer pain.

A. 5%

B. 10%

C. 20%

D. 25%

2. Pain signals are carried along which of the following fibers?

A. A[delta] and C

B. A[delta] only

C. A[delta] and A[beta]

D. A[beta] and C

3. Modulation is which of the following?

A. The translation of noxious stimuli into nociceptive impulses

B. The phase in which nociceptive impulses are conveyed from the site of injury to the dorsal horn of the spine and then to the brain

C. The process of inhibition or amplification of nociceptive impulses

D. The influence of other steps and the patient's psychologic input resulting in the subjective feeling of pain

4. Which of the following is true of Melzack's neuromatrix theory?

A. The "gate" is always open in this theory.

B. Early-life pain experiences influence reactions to pain throughout life.

C. Only patients with neurological disorders experience pain more negatively than do others.

D. The "gate" is always closed in this theory.

5. Which of the following best describes second pain?

A. Transmitted by C fibers, it is a brief, sharp sensation.

B. Transmitted by A[delta] fibers, it is a brief, sharp sensation.

C. Transmitted by A[delta] fibers, it is a longer-lasting, burning or aching pain.

D. Transmitted by C fibers, it is a longer-lasting, burning or aching pain.

6. Which of the following best describes allodynia?

A. It is an exaggerated response to a moderately noxious stimulus.

B. It is a pain response to a normally innocuous stimulus.

C. It is a warning sign that central sensitization may occur in the near future.

D. It is always a transient condition that ends once the noxious stimulus is removed.

7. At least --% of patients have been observed to experience persistent pain following amputation, coronary artery bypass surgery, or thoracotomy.

A. 30

B. 20

C. 15

D. 5

8. Which of the following best describes the concept of a "medical home"?

A. A hospice center for patients with painful terminal conditions B. A single medical center where all members of a patient's care team work

C. A single clinician who coordinates all aspects of a patient's care

D. Modifications to a patient's home to accommodate his or her limitations

9. Which of the following is true regarding smoking among patients with chronic noncancer pain?

A. Use of nicotine products has been associated with increased pain.

B. Use of nicotine products has been associated with increased pain and reduced efficacy of some medications used to treat pain.

C. Use of nicotine products has been associated with reduced efficacy of some medications used to treat pain, but has no effect on pain itself.

D. Although use of nicotine products has been associated with reduced efficacy of some medications used to treat pain, it actually reduces pain.

10. Which of the following best describes adjuvant analgesics?

A. Drugs primarily indicated for uses other than analgesia

B. All nonopioid analgesic drugs

C. All drugs used along with opioid analgesics

D. Drugs added to existing analgesic regimens

11. The most common adverse effects of opioids are which of the following?

A. Respiratory depression

B. Accelerated heart rate

C. Skin irritation, particularly pruritus

D. Gastrointestinal symptoms, especially constipation

12. Which of the following best describes the most important trait of an analgesic with a dual mechanism of action?

A. It has twice the potency of an analgesic with a single mechanism of action.

B. It may have twice the number of adverse effects as does an analgesic with a single mechanism of action.

C. It has an effect on both the ascending and the descending pain pathways.

D. It uses whichever mechanism is applicable to a specific type of pain.


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Table 1. Differences Between Acute and Chronic Pain z

Acute                            Chronic

Identifiable cause (eg,          Typically due to chronic
injury, surgery, disease)        condition or may have no
                                 obvious cause

Sudden (or recent) onset         Often undetermined onset

Short duration (<1 month)        Persists beyond healing
                                 ([greater than or equal
                                 to] 3 months)

Variable intensity correlated    Prolonged functional
with severity of condition       impairment

Serves as alert of harm          May be accompanied by
                                 ongoing or no tissue damage

Usually resolves with            Does not resolve
resolution of cause              spontaneously

Table 2. Consequences of Unrelieved Pain (5,6)

Area                   Effects of Pain

Overall quality        Reduced confidence in
of life                abilities, diminished
                       enjoyment of activities and
                       personal relationships,
                       impaired sleep

Employment             Reduced work productivity,
                       increased absenteeism, lost
                       income, job insecurity

Endocrine/metabolic    Weight loss, fever, shock

Cardiovascular         Angina, myocardial infarction,
system                 deep vein thrombosis

Respiratory system     Atelectasis, pneumonia

Gastrointestinal       Constipation, anorexia, ileus

Musculoskeletal        Muscle spasm, immobility,
system                 weakness, fatigue

Immune system          Infection

Genitourinary system   Decreased urine output,
                       hypertension (fluid
                       retention), electrolyte

Table 3. Grading the Evidence (9)

Quality     Description

  High      Includes consistent results from
            well-designed, well-conducted studies that
            directly assess effects on health outcomes in
            representative populations ([greater than or
            equal to] 2 high-quality randomized
            controlled trials, [greater than or equal to]
            2 prospective risk-prediction studies, or
            several observational studies with no
            significant methodologic flaws that show
            large effects)

Moderate    Sufficient to determine effects on health
            outcomes, but evidence strength is limited by
            number, quality, size, or consistency of
            studies; generalizability to routine
            practice; or indirect nature of evidence
            ([greater than or equal to] 1 trial or
            prospective risk-prediction study with >100
            subjects; [greater than or equal to] 2
            higher-quality trials with some
            inconsistency; [greater than or equal to] 2
            lower-quality trials or prospective
            risk-prediction studies; or multiple observa-
            tional studies with no significant
            methodologic flaws that show large effects)

  Low       Insufficient to assess effects on health
            outcomes because of limited number or power
            of studies; large unexplained inconsistency
            between studies; important flaws in study
            design or conducts; gaps in evidence chain;
            or lack of information on important health

Table 4. Screening Tools (9,23-25)

Acronym   Full Title              Description/Comment(s)

SOAPP     Screener and Opioid     14-item tool to help
          Assessment for          clinicians determine
          Patients with Pain      frequency and extent of
                                  monitoring that each
                                  patient on long-term
                                  opioid therapy should

ORT       Opioid Risk Tool        5-item instrument to help
                                  clinicians determine
                                  likelihood of a patient's
                                  future drug abuse

DIRE      Diagnosis,              Instrument scoring
          Intractability,         several patient
          Risk Efficacy           characteristics to
                                  determine who would and
                                  who would not be suitable
                                  candidates for long-term
                                  opioid therapy

OAS       Opioid Attractiveness   17-item scale for
          Scale                   patients to use to rate
                                  abuse potential of
                                  individual opioids

STAR      Screening Tool for      14 true-or-false
          Addiction Risk          questions about personal
                                  and family drug-use
                                  history, current personal
                                  habits and status

Table 5. Nonopioid Analgesics (2,5,7,35)

Class                  Advantages                  Disadvantages

Acetaminophen          Superior GI and CV safety   Potential
                       to that of NSAIDs; no       hepatotoxicity; not
                       effect on platelet          anti-inflammatory
                       aggregation and related
                       bleeding risk

Aspirin                Established nonopioid       Risk of GI AEs,
                       analgesic                   inhibition of
                                                   aggregation; largely
                                                   replaced by newer

Nonselective NSAIDs    Have analgesic,             Dose ceiling above
(eg, ibuprofen,        antipyretic, and anti-      which AEs increase
naproxen)              inflammatory activity       but analgesia does
                                                   not (unlike
                                                   p-agonist opioids);
                                                   interfere with
                                                   aggregation; mild to
                                                   severe GI AEs;
                                                   chance of
                                                   and renal events,
                                                   especially in
                                                   at-risk population

COX-2-selective        Low risk of serious GI      AEs with long-term-
inhibitors (eg,        AEs during short-term       use similar to those
celecoxib)             use; no effect on           of nonselective
                       platelet aggregation, so    NSAIDs with the
                       less concern with acute     exception of
                       bleeding for at-risk        platelet effects

Topical agents (eg,    Act locally, so systemic    Local skin
lidocaine patch 5%,    absorption and side         irritation; pain
capsaicin cream,       effects are rare; no drug   relief only in area
diclotenac gel 1%)     interactions; effective     of administration
                       in neuropathic and
                       musculoskeletal pain

Tricyclic              Particularly effective in   Common AEs include
antidepressants (eg,   neuropathic pain and non-   dry mouth,
amitriptyline,         neuropathic pain            constipation,
imipramine)            accompanied by insomnia     urinary retention,
                       or depression               sedation, weight

Antiepileptics leg,    Limit neuronal              Common AEs include
gabapentin,            excitation, enhance         dizziness,
pregabalin)            inhibition; effective in    drowsiness, fatigue,
                       neuropathic and lancing     edema, nausea,
                       pain                        sedation, weight

GI= gastrointestinal: CV-cardiovascular: NSAIDs=nonsteroidal
anti-inflammatory drugs: AE=adverse effect: COX=cyclooxygenase.

Table 6. Opioid Metabolism (32,38)

                       Cytochrome P (CYP) Isoform

Agent                  Substrate              Inhibitor

Codeine                3A4, 2D6                  2D6
Oxycodone                 2D6
Fentanyl                  3A4                    3A4
Hydrocodone               2D6
Morphine                  2D6
Buprenorphine             3A4            1A2, 2A6, 2C19, 2D6
Meperidine          2B6, 2C19, 2D6            2D6, 3A4
Tramadol             2D6, 2B6, 3A4
Tapentadol       (only 15%) 2C9 + 2C19
                     (13%), 2D6 (2%)
Oxymorphone            Phase II
Hydromorphone          Phase II

Written communication, Robert L. Barkin, PharmD. September 2009.

Figure 1. Duration of Pain, US Adults, NHANES, 1999-2002 (3)

<1 month        32%
1-3 months      12%
3-12 months     14%
12+ months      42%

NHANES=National Health and Nutrition Examination Survey.

Note: Table made from pie chart.
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Title Annotation:chronic pain
Publication:Family Practice News
Article Type:Report
Geographic Code:1USA
Date:Apr 15, 2010
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