Risks associated with tamoxifen and raloxifene limit the appeal of these agents for prevention of primary breast cancer.

The selective estrogen receptor modulators (SERMs) tamoxifen (TAM) and raloxifene (RAL) — and the selective tissue estrogenic activity regulator tibolone — are all associated with lower risk for primary invasive breast cancer. TAM and RAL are approved in the U.S. for chemoprophylaxis in high-risk women (RAL in postmenopausal women only). In a review of seven placebo-controlled trials and one head-to-head trial involving women without histories of breast cancer, investigators assessed the effectiveness and safety of these three agents (tibolone is not available in the U.S.).

Overall, TAM and RAL lowered the incidence of invasive breast cancer by 7 to 10 women per 1000 annually (risk ratios, 0.70 and 0.44, respectively). In both pre- and postmenopausal women, these SERMs reduced risk for estrogen-receptor–positive tumors (but not estrogen-receptor–negative tumors), noninvasive breast cancers, and mortality from breast cancer. Both agents also reduced risk for osteoporotic fractures. TAM and RAL raised risk for venous thromboembolic events (VTEs) by 4 to 7 women per 1000 annually (RRs, 1.93 and 1.60, respectively). TAM (but not RAL) raised the endometrial cancer risk (RR, 2.13) and was also associated with excess risk for abnormal uterine bleeding and hysterectomy for benign disease. Both SERMs were associated with greater likelihood of hot flashes.

Comment: In the U.S., tamoxifen is most often prescribed as adjuvant endocrine therapy following initial treatment for estrogen-receptor–positive breast cancer in pre- and postmenopausal women; raloxifene is approved for prevention of osteoporotic fractures in postmenopausal women. Because most trial participants were white and relatively healthy, the relevance of these findings to women of other ethnicities or with comorbidities is uncertain. Risks and side effects associated with SERMs have limited their use for breast cancer chemoprophylaxis in the U.S. In particular, VTE risk is an issue in overweight and older women — and risk for malignant and benign gynecologic disease is cause for concern in premenopausal women with intact uteri. Clinicians of women at risk for breast cancer should help those who are considering chemoprophylaxis to understand the benefits and risks of SERMs in the context of their own personal circumstances. Moreover, aromatase inhibitors represent a potential alternative that is now being evaluated.

Comprehensive treatment for chronic pain must address both physical and psychological aspects.

Pain is a leading reason that people seek medical care. Annually, pain is estimated to burden the U.S. economy with $100 billion in direct costs and $61 billion in productivity losses. These losses, which amount to a mean of 4.6 hours weekly, are largely due to diminished performance at work.¹ Perhaps more significant, but more difficult to quantify, is the emotional distress and diminished quality of life that pain inflicts on individuals and their loved ones.

WHAT IS PAIN?

Pain, as defined by the International Association for the Study of Pain is “an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage.”² Thus, pain is an experience that comprises a physical sensory component and an affective cognitive component. The physical element involves a nociceptive, neuropathic, or inflammatory stimulus that is transmitted via the spinal cord to the thalamus and then to areas of the cerebral cortex, where it is perceived. Acute pain serves a biological purpose as an alert to potential, immediate, or ongoing injury.

Chronic pain is pathologic, serves no biological purpose, and can result from peripheral sensitization, in which processes (such as changes in gene expression in the dorsal root ganglia) augment the synthesis of various peripheral nociceptors. In turn, inputs to the dorsal horn of the spinal cord are amplified, leading to activation of N-methyl-D-aspartate (NMDA) receptors and subsequent spinal cord hyperexcitability. Destruction of inhibitory interneurons and sprouting of nerve fibers at the level of the dorsal horn also can contribute to central sensitization; in addition, disruption of descending inhibitory neural pathways can trigger central hypersensitivity and chronic pain.³

Chronic pain can persist after an initial injury has healed, or it can result from ongoing pathologic processes. Although specific periods (typically 6 months) often are used to define chronic pain, a more appropriate definition of the condition is simply pain that persists longer than it should. Chronic pain often involves neural activity in specific brain areas that are distinct from those that mediate acute pain; for example, unrelenting back pain is processed by areas that also process negative emotions.⁴ In addition, chronic pain can have widespread effects on overall brain functioning, thereby causing depression, anxiety, and decision-making difficulties in ways that acute pain does not.

WOMEN AND PAIN

Conditions such as headache, pelvic pain, rheumatoid arthritis, and facial pain are more common in women than in men; accordingly, women are two to three times more likely than men to suffer from chronic pain. Compared with men, women also tend to perceive pain as more severe and to report lower pain thresholds and higher pain ratings in research studies. Such sex differences could be secondary to the influence of hormones, family history, traditional sex roles, cognitive factors, and how the central nervous system processes pain.⁵

INTERDISCIPLINARY TREATMENT OF CHRONIC PAIN

Comprehensive treatment of chronic pain must address both physical and psychological aspects; thus, interdisciplinary approaches to pain management involve medical management, physical therapy, occupational therapy, biofeedback, vocational and recreational therapy, and psychological counseling.

Rational polypharmacy (evidence-based use of multiple medications) is a cornerstone of medical management of pain syndromes, which can encompass sleep and mood disorders. Treatment options include nonsteroidal anti-inflammatory agents, antiepileptic drugs such as gabapentin (for neuropathic pain), antidepressants, and opioid drugs. Use of chronic opioid therapy has risen substantially, along with concerns about drug abuse and addiction; accordingly, treatment recommendations have been developed by the American Pain Society and the American Academy of Pain Medicine to provide guidance about patient selection, risk factors for abuse, and opioid management plans.⁶ Chronic opioid treatment is appropriate if analgesia is achieved, adverse side effects do not occur, activities of daily living improve, and aberrant behavior or signs of abuse are not present (sometimes referred to as the four A’s). In addition to documentation of the four A’s, clinicians’ use of opioid contracts with patients, as well as random urine screens, all help to justify prescribing these agents as part of therapy for patients with chronic pain. Other medical strategies involve steroid injections (epidural or delivered directly to affected joints) to treat pain flares, and, when indicated, surgical approaches.

Physical therapy serves to allay the patient’s fear of movement; to teach the difference between “hurt” and “harm” sensations; to increase endurance, range of motion, and tolerance for sitting, standing, and walking; and to improve posture and strength. Occupational therapy addresses body mechanics, pacing, functional mobility and activities of daily living, and ergonomic modifications in the workplace. Biofeedback helps the patient to master diaphragmatic breathing and progressive muscle relaxation with the goals of alleviating muscle tension, reducing physical and emotional distress, and encouraging mindfulness of pain in an effort to divert attention away from it.

Managing pain largely entails attending to its psychological features and their impingement on overall emotional status. Sleep disturbances, anxiety, and depression can be treated with psychotherapy and, when required, pharmacologic agents. Along with medical management, cognitive-behavioral therapy (CBT) is often a mainstay of treatment.⁷ CBT is based on the theory that thoughts affect feelings and behaviors, which, in turn, influence how one experiences pain. CBT teaches individuals how to identify negative dysfunctional pain-related thoughts and how to replace them with more-adaptive thoughts. Ideally, one learns coping skills that can be applied to daily situations, including pain flares.

A key goal of CBT — indeed, of all the therapies for chronic pain — is to foster the belief that patients have the power to manage their pain by improving their physical abilities and by learning how to control their thoughts, behaviors, and reactions. Having a healthy sense of command of oneself includes being both physically and socially active and integrated. Unremitting pain leads to lower physical activity levels, resulting in diminished function and greater likelihood of depression; maintaining higher activity levels leads to less pain, thereby breaking the cycle.

Maintaining a sense of control is undeniably challenging for women who are in continual pain. Isolation and depression commonly accompany chronic pain conditions, which makes treatment difficult. Women must learn to maintain direction over their own lives and take time to care for themselves while also meeting the challenges of employment, caring for their families, and remaining socially integrated. Being able to do all of this, in addition to handling a debilitating condition, can be demoralizing and exhausting — physically, emotionally, and financially. Likewise, managing chronic pain conditions can be challenging and potentially draining for clinical pain-care teams. The treating clinician has a responsibility not only to educate the patient that her chronic pain is a disease but also to stop ongoing and unnecessary laboratory and radiologic testing after the diagnosis has been made definitively.

CONCLUSION

Collaboration among therapists, psychologists, and other supportive resources is crucial to delivering effective pain treatments. Helping women with chronic pain to take ownership of their conditions and to actively curb physical and emotional aspects will boost their functional mobility, productivity, and quality of life while also shrinking the associated financial burden.