Neuropathy refers to a "disturbance of function or pathological change in a nerve: in one nerve, mononeuropathy; in several nerves, mononeuropathy multiplex; if diffuse and bilateral, polyneuropathy." 1 Neuropathies are generally associated with sensory or motor dysfunction, but not all neuropathies are painful. The International Association for the Study of Pain defines neuropathic pain as "pain initiated or caused by a primary lesion or dysfunction in the nervous system" 1 that disrupts impulse transmission and modulation of sensory input.

Most chronic pain syndromes and neuropathies experienced by disease-free survivors of cancer originate from an injury to peripheral nerves from surgical trauma, 2-5 neurotoxicity of chemotherapeutic agents, 6, 7 and radiation-induced damage to nerves (see Table 1, page 40). 8 Other sources of persistent or intermittent pain 9-11 include

Chronic pain after mastectomy or lumpectomy with axillary node dissection is reported in about 20% of women. 12 Believed to be related to intercostobrachial nerve trauma, this pain, often called postmastectomy pain syndrome (PMPS), is characterized by burning, shooting, and electric shock-like sensations in the skin around the surgical sites. PMPS can interfere with both occupational and domestic activities. 13 Risk factors for PMPS are unclear, but recent data suggest that it may be more common among younger women (ages 30 to 49 years) and women who are overweight. 5, 14 Findings from a study of 134 women evaluated an average of 35 months following mastectomy and lumpectomy revealed PMPS among women who had a lumpectomy without an axillary node dissection and those who had intercostobrachial nerve-sparing surgery. 15 Health outcomes measured by the Short Form-36 Health Survey in 113 women seven to 12 years following mastectomy show significantly poorer scores in 59 women with persistent PMPS compared to 54 whose pain had resolved over time. 5 In a study of breast cancer survivors, ethnicity correlated with PMPS-like pains, fatigue, and depression; African American and Latina women reported increased rates of pain than did whites. 16

PMPS is treated pharmacologically. Topical capsaicin has been shown to be effective for associated itching and pain. 17 Administration of venlafaxine (Effexor) the night before surgery and postoperatively for two weeks was associated with decreased pain with movement and a decreased incidence of chest wall and arm pain six months postsurgery. 18 Early physical therapy may help to prevent the functional limitations in the affected arm and in cases of frozen shoulder (a condition characterized by pain, stiffness, and limited motion). 18

Thoracotomy.

Between 50% and 80% of people undergoing a thoracotomy experience chronic pain several months after the procedure, 4, 19 and 30% of survivors may still have pain four to five years after surgery. 20 Neuropathic pain is experienced most frequently along the surgical scar, although some patients may also experience myofascial pain or frozen shoulder. The syndrome is believed to be caused by injury to the intercostal nerve. 21 The pain is generally mild and decreases in severity over time, but about 5% of thoracotomy survivors report severe disabling pain. 19, 22 Methods to prevent long-term pain include selecting the most minimally invasive procedure, such as video-assisted thoracotomy, and aggressively treating postoperative pain with multimodal therapy. 4 The incidence and severity of pain at six months postthoracotomy have been significantly reduced with thoracic epidural analgesia with morphine and bupivacaine (Marcaine) before and during surgery. 23 The combination of pharmacologic, behavioral, and interventional (for example, anaesthesia-based) procedures produces the best results. 21

Head and neck cancer.

Surgically induced pain and loss of function have been documented in head and neck cancer survivors. 2, 24 One study reported severe pain after surgery of both nociceptive (myofascial and soft tissue) and neuropathic origin in 52% of subjects (21 out of 40) with a mean duration of pain complaints of 26.9 weeks (one to 92 weeks). 2 Loss of sensation and decreased range of motion have also been observed. 11

Amputation.

Postamputation pain often has two components: one is localized to the amputated area, and the other, referred to as phantom pain, is mediated by mechanisms in the central nervous system producing neuropathic central pain. 3, 10 Amputation of limbs and other body parts such as the breast can cause phantom pain. As many as two-thirds of limb amputees report phantom pain six months after amputation and 5% to 10% experience persistent severe pain. 25 One study reported phantom pain in about 60% of survivors two years after surgery. 26 Phantom pain does not respond well to conventional analgesics, but neuropathic pain drugs such as anticonvulsants and tricyclic antidepressants are sometimes effective. Small-scale clinical trials showed oral dextromethorphan (Delsym), an N-methyl-D-aspartate receptor antagonist, to be effective in mitigating phantom limb pain in cancer survivors. 27, 28

RADIATION-RELATED PAIN AND NEUROPATHY

Radiation-induced pain syndromes such as myelopathy, which is characterized by damage to nerve tracts along the spinal cord and tissue necrosis or damage, while less common with advances in radiotherapy, are not well described. Refinements in technical applications of X-rays, computerized tomography scans, magnetic resonance imaging, positron emission tomography scans, and electronic portal imaging are among the improvements in the ability to localize tumors and spare normal tissue from the effects of radiation exposure. 29 Combined treatment modalities (radiation therapy with chemotherapy) also minimize the need for aggressive radiotherapy. Ongoing research is needed to evaluate these advances in minimizing long-term toxicities. 30 The diagnosis of radiation-induced pain syndromes, specifically myelopathy and other tissue damage, can often be obscured by the recurrence of tumor in the irradiated area, which can also cause pain and neurologic impairment. 8

Survivors treated in past decades may experience chronic myelopathy, which is characterized by a burning sensation localized to the spinal region and can first occur up to 14 months after treatment. 9 Limited information is available about nerve damage with early use of radiotherapy; however, one study of 71 cancer survivors treated between 1963 and 1965 found that 92% experienced paralysis of the affected arm up to 34 years after radiation. 31 By tracking the time course for late effects, these investigators documented 86% with fibrosis and 14% who had already developed brachial plexus neuropathy at two years after treatment. Nineteen percent experienced grade 3 to 4 pain (on a scale of 0, no pain, to 4, very severe pain) an average of 3.1 years following therapy. A recent case report described a patient with severe cervical neuropathy three decades after being treated for Hodgkin lymphoma. 32

Other sources of pain have been documented among survivors after radiation therapy. In a clinical trial involving 143 survivors of cervical and endometrial cancer, which was conducted to examine the effects of dietary modifications on radiation-induced diarrhea three to four years after treatment, lower back pain was observed in 17 women and pains in the hips and thighs in 14 women. 33 The etiology of these pains was unclear. According to another study, 12% of 195 survivors treated with intraoperative electron radiation for a variety of cancers suffered from peripheral neuropathy five years after treatment. 8 Pelvic radiation for prostate, cervical, and endometrial carcinomas leads to chronic proctitis in about 2% to 5% of cancer survivors, but there does not seem to be a relationship between acute proctitis and the development of chronic pain. 34 Pain on defecation can occur with chronic proctitis, which can be treated conservatively with antidiarrheal medications, topical steroids, and sucralfate enemas. 35

CHEMOTHERAPY-RELATED PAIN AND NEUROPATHY

Several classes of chemotherapeutic drugs such as the plant alkaloids, including vincristine (Oncovin) and vinblastine (Velban); taxanes such as paclitaxel (Taxol); the platinum-based compounds cisplatin (Platinol), carboplatin (Paraplatin) and oxaliplatin (Eloxatin); and the antimitotics methotrexate (Trexall), cytosine arabinoside (Cytosar-U), and fluorouracil (Adrucil) may cause peripheral neuropathy. Animal experiments have suggested the biological mechanisms for nerve damage from drugs such as paclitaxel, vincristine, and cisplatin. 36-38 Clinicians take this adverse effect very seriously, as it can interfere with optimal dosing, delay sequencing of therapy, or necessitate discontinuation of treatment.

Prevalence.

Estimates for the incidence of chemotherapy-induced peripheral neuropathies vary considerably. This development of both short-and long-term toxicity is highly dependent on several factors such as age, single-dose intensity, cumulative dose, combinations of neurotoxic agents, coexisting neuropathies (for example, diabetic neuropathy), genetic susceptibility, alcohol abuse, impaired drug metabolism, and excretion of active metabolites. 7, 39 Hundreds of studies document the occurrence of neurotoxicity during treatment with various agents and combination regimens. Yet few well-designed longitudinal or cross-sectional studies capture the number of cancer survivors who continue to experience pain and functional limitations years after therapy or the time course, severity, and patterns of neurologic impairment. Extensive reviews have been published to summarize the literature on this widespread problem. 6, 7, 39, 40

Characterization.

Severity, characteristics, and duration of symptom experiences vary greatly with neurotoxic chemotherapeutic agents. For example, paclitaxel can induce sensory impairment and pain, whereas vincristine often causes a sensorimotor neuropathy that also includes motor dysfunction such as foot drop. 39 Peripheral neuropathies generally affect the distal parts of extremities symmetrically and are characterized by a "stocking and glove" phenomenon of the feet and hands and with paresthesia or dysesthesia, including sensations of numbness or tingling. Vincristine- and platinum-containing compounds can also induce autonomic symptoms such as orthostatic hypotension, constipation, paralytic ileus, and bladder dysfunction. 40

The time course for the onset of peripheral neurotoxicity has been well described for some agents. For example, patients receiving cisplatin develop signs of neuropathy about one month after the first course of therapy. 41 It is more variable with oxaliplatin, which can typically produce symptoms within 30 to 60 minutes after the infusion. 42 Delayed neurotoxicity has not been well studied, but some survivors experience persistent residual effects of chemotherapy, including paresthesia, dysesthesia, pain, or sensory and motor impairment months and even years after treatment is discontinued. 43-45 Several recent reviews have addressed the diagnosis and assessment of chemotherapy-induced peripheral neuropathies. 7, 39, 46

Treatment.

Anticonvulsants, tricyclic antidepressants, and opioids can be effective for alleviating neuropathic pain. 47 Novel pharmacologic agents such as neuroprotective compounds (examples are amifostine [Ethyol]; glutamine, an amino acid; and glutathione, an antioxidant and product of glutamine metabolism) and neurotrophic factors (such as nerve growth factor) can also be effective. 47 Some data are available to show that glutamine, which acts as a substrate for dividing cells, helps prevent or minimize peripheral neuropathy related to paclitaxel-induced neurotoxicity. 48 Vitamin E has shown some promise in prophylaxis of chemotherapy-induced peripheral neuropathy with cisplatin and paclitaxel. 49 Less is known about nonpharmacologic and alternative therapies. In a clinical case report, two patients benefited from an implanted spinal cord stimulator that alleviated pain, increased leg flexibility, and led to improvements in sensory threshold detection. 50 Exercise and occupational therapy can be helpful in restoring function of extremities, but studies of their effectiveness have mostly been done in the early treatment phase. Other nutritional supplements such as evening primrose oil, alpha-lipoic acid, and capsaicin may be effective with advanced peripheral neuropathy from diabetes but have not been adequately studied in cancer survivors. 45

GAPS IN THE SCIENCE AND BARRIERS IN PRACTICE

Evidence is growing to explain interpatient symptom variability; to identify incidence, risk, and severity; and to understand the biopsychosocial impact of posttreatment pain syndromes. Most of the research has been conducted among survivors of breast, lung, head and neck, and colorectal cancers. 11, 15, 21, 24, 51 But there is still a significant void in scientific knowledge and practice-based experience about survivors' responses to various pain-relieving interventions.

Few studies have examined the efficacy of neuropathic pain agents in treating long-term cancer survivors. Anticonvulsants, tricyclic antidepressants, and chronic opioid therapy for treatment-induced pain syndromes, especially postmastectomy, postthoracotomy, and chemotherapy-induced peripheral neuropathy, should be researched. Similarly, few studies document success rates of analgesics, specific intervention techniques, cognitive and behavioral therapies, exercise, and other alternative therapies such as nutraceuticals. Moreover, the benefits of specialized pain management through referrals to pain clinics or centers have not yet been realized. Criteria for when to refer patients with cancer-related pain for interventional therapy and nonpharmacologic consultations are outlined in the National Cancer Center Network Clinical Practice Guidelines in Oncology (see "Adult Cancer Pain" in the section titled "Guidelines for Supportive Care"). 52

In July 2002 the Office of Medical Applications of Research and the National Institutes of Health created a group of pain and oncology experts to evaluate the symptom cluster of pain, fatigue, and depression. The quality of evidence was appraised, gaps in research identified, and future research priorities established. Subsequently, Carr and colleagues published an extensive review of available evidence on the efficacy of treatments for cancer-related pain. 53 Even though these evidence-based summaries focus predominantly on pain from disease progression, the effectiveness of interventions can also be generalized to pain experienced by survivors. While there are no specific guidelines for the treatment of pain and neuropathy in survivors, information can be obtained from evidence-based guidelines summarizing scientific advances in the diagnosis and understanding of neuropathic pain mechanisms and therapeutic approaches. 54 Other sources offer useful information on pharmacologic agents used to treat neuropathic pain. 55, 56

SUPPORTIVE CARE FOR SURVIVORS AND FAMILIES

Pain management in cancer survivors raises some specific issues (see Table 2, page 42). Lyne and colleagues emphasized the importance of educational and financial issues in the management of pain with survivors. 9 The problem of "don't ask, don't tell" may prevent patients from freely reporting any symptoms of pain and signs of neurologic impairment.

It is the responsibility of all health care professionals caring for cancer survivors to educate them about the possibility of long-term consequences of cancer and cancer treatments. Teaching survivors about the potential for pain and neurologic damage creates an environment in which they are more likely to report their symptoms. On a more practical level, education can focus on promoting self-management. 46, 57 Survivors can learn to protect hands and feet, prevent falls, assess water temperature to prevent burns, use protective gloves and pot holders, keep rooms well lit, clear walkways, and use nonskid mats in showers and bathtubs. 46 A 2002 article in Cancer Practice offers a detailed listing of resources available to posttreatment cancer survivors to assist them in engaging in self-help activities and interventions. 58

Almadrones and associates tested two instruments to measure functional status and neuropathy in ovarian cancer patients: the Gynecological Oncology Group Performance Status Scale and the Peripheral Neuropathy Scale. 59 These instruments provide pertinent questions to help patients communicate their functional limitations and performance in activities of daily living and establish criteria for evaluating the presence and severity of peripheral neuropathy-related symptoms. Neurologic examinations should be conducted, which include identifying the presence of sensitivity to touch or numbness of the affected areas, motor weakness, abnormal reflexes in deep tendons, disturbances in gait and balance, and orthostatic hypotension. 60 Lastly, treatment options that are known to be effective for neuropathic pain should be considered when nonpharmacologic approaches such as exercise, occupational therapy, and alternative and complementary therapies alone are not helpful in relieving pain and restoring optimal function.

What to Ask Cancer Survivors

1. Merskey H, Bogduk N, editors. Classification of chronic pain: descriptions of chronic pain syndromes and definitions of pain terms. 2nd ed. Seattle, WA: IASP Press; 1994. [Context Link]

2. Chua KS, et al. Pain and loss of function in head and neck cancer survivors. J Pain Symptom Manage 1999;18(3):193-202. [Context Link]

3. Marchettini P, et al. Iatrogenic painful neuropathic complications of surgery in cancer. Acta Anaesthesiol Scand 2001;45(9):1090-4. [Context Link]

4. Karmakar MK, Ho AM. Postthoracotomy pain syndrome. Thorac Surg Clin 2004;14(3):345-52. [Context Link]

5. Macdonald L, et al. Long-term follow-up of breast cancer survivors with post-mastectomy pain syndrome. Br J Cancer 2005;92(2):225-30. [Context Link]

6. Polomano RC, Bennett GJ. Chemotherapy-evoked painful peripheral neuropathy. Pain Med 2001;2(1):8-14. [Context Link]

7. Visovsky C. Chemotherapy-induced peripheral neuropathy. Cancer Invest 2003;21(3):439-51. [Context Link]

8. Azinovic I, et al. Long-term normal tissue effects of intraopera-tive electron radiation therapy (IOERT): late sequelae, tumor recurrence, and second malignancies. Int J Radiat Oncol Biol Phys 2001;49(2):597-604. [Context Link]

9. Lyne ME, et al. Pain management issues for cancer survivors. Cancer Pract 2002;10 Suppl 1:S27-32. [Context Link]

10. Portenoy RK, Conn M. Cancer pain syndromes. In: Bruera E, Portenoy RK, editors. Cancer pain: assessment and management. New York: Cambridge University Press; 2003. p. 89-110. [Context Link]

11. van Wilgen CP, et al. Morbidity of the neck after head and neck cancer therapy. Head Neck 2004;26(9):785-91. [Context Link]

12. Ververs JM, et al. Risk, severity and predictors of physical and psychological morbidity after axillary lymph node dissection for breast cancer. Eur J Cancer 2001;37(8):991-9. [Context Link]

13. Stevens PE, et al. Prevalence, characteristics, and impact of postmastectomy pain syndrome: an investigation of women's experiences. Pain 1995;61(1):61-8. [Context Link]

14. Bosompra K, et al. Swelling, numbness, pain, and their relationship to arm function among breast cancer survivors: a disablement process model perspective. Breast J 2002;8(6):338-48. [Context Link]

15. Carpenter JS, et al. Risk factors for pain after mastectomy/lumpectomy. Cancer Pract 1999;7(2):66-70. [Context Link]

16. Eversley R, et al. Post-treatment symptoms among ethnic minority breast cancer survivors. Oncol Nurs Forum 2005;32(2):250-6. [Context Link]

17. Hautkappe M, et al. Review of the effectiveness of capsaicin for painful cutaneous disorders and neural dysfunction. Clin J Pain 1998;14(2):97-106. [Context Link]

18. Reuben SS, et al. Evaluation of efficacy of the perioperative administration of venlafaxine XR in the prevention of postmastectomy pain syndrome. J Pain Symptom Manage 2004;27(2):133-9. [Context Link]

19. Perttunen K, et al. Chronic pain after thoracic surgery: a follow-up study. Acta Anaesthesiol Scand 1999;43(5):563-7. [Context Link]

20. Dajczman E, et al. Long-term postthoracotomy pain. Chest 1991;99(2):270-4. [Context Link]

21. Erdek MA, Staats PS. Chronic pain and thoracic surgery. Thorac Surg Clin 2005;15(1):123-30. [Context Link]

22. Gotoda Y, et al. The morbidity, time course and predictive factors for persistent post-thoracotomy pain. Eur J Pain 2001;5(1):89-96. [Context Link]

23. Senturk M, et al. The effects of three different analgesia techniques on long-term postthoracotomy pain. Anesth Analg 2002;94(1):11-5. [Context Link]

24. Pourel N, et al. Quality of life in long-term survivors of oropharynx carcinoma. Int J Radiat Oncol Biol Phys 2002;54(3):742-51. [Context Link]

25. Melzack R. Phantom limb pain: implications for treatment of pathologic pain. Anesthesiology 1971;35(4):409-19. [Context Link]

26. Jensen TS, et al. Immediate and long-term phantom limb pain in amputees: incidence, clinical characteristics and relationship to pre-amputation limb pain. Pain 1985;21(3):267-78. [Context Link]

27. Ben Abraham R, et al. Dextromethorphan for phantom pain attenuation in cancer amputees: a double-blind crossover trial involving three patients. Clin J Pain 2002;18(5):282-5. [Context Link]

28. Ben Abraham R, et al. Dextromethorphan mitigates phantom pain in cancer amputees. Ann Surg Oncol 2003;10(3):268-74. [Context Link]

29. Bucci MK, et al. Advances in radiation therapy: conventional to 3D, to IMRT, to 4D, and beyond. CA Cancer J Clin 2005;55(2):117-34. [Context Link]

30. Gordils-Perez J, et al. Advances in radiation treatment of patients with breast cancer. Clin J Oncol Nurs 2003;7(6):629-36. [Context Link]

31. Johansson S, et al. Timescale of evolution of late radiation injury after postoperative radiotherapy of breast cancer patients. Int J Radiat Oncol Biol Phys 2000;48(3):745-50. [Context Link]

32. McFarlane VJ, et al. Cervical neuropathy following mantle radiotherapy. Clin Oncol (R Coll Radiol) 2002;14(6):468-71. [Context Link]

33. Bye A, et al. Health-related quality of life and occurrence of intestinal side effects after pelvic radiotherapy--evaluation of long-term effects of diagnosis and treatment. Acta Oncol 2000;39(2):173-80. [Context Link]

34. Ajlouni M. Radiation-induced proctitis. Curr Treat Options Gastroenterol 1999;2(1):20-6. [Context Link]

35. Colwell JC, Goldberg M. A review of radiation proctitis in the treatment of prostate cancer. J Wound Ostomy Continence Nurs 2000;27(3):179-87. [Context Link]

36. Aley KO, et al. Vincristine hyperalgesia in the rat: a model of painful vincristine neuropathy in humans. Neuroscience 1996;73(1):259-65. [Context Link]

37. Boyle FM, et al. Amelioration of experimental cisplatin and paclitaxel neuropathy with glutamate. J Neurooncol 1999;41(2):107-16. [Context Link]

38. Polomano RC, et al. A painful peripheral neuropathy in the rat produced by the chemotherapeutic drug, paclitaxel. Pain 2001;94(3):293-304. [Context Link]

39. Dropcho EJ. Neurotoxicity of cancer chemotherapy. Semin Neurol 2004;24(4):419-26. [Context Link]

40. Quasthoff S, Hartung HP. Chemotherapy-induced peripheral neuropathy. J Neurol 2002;249(1):9-17. [Context Link]

41. LoMonaco M, et al. Cisplatin neuropathy: clinical course and neurophysiological findings. J Neurol 1992;239(4):199-204. [Context Link]

42. Verstappen CC, et al. Neurotoxic complications of chemotherapy in patients with cancer: clinical signs and optimal management. Drugs 2003;63(15):1549-63. [Context Link]

43. Strumberg D, et al. Evaluation of long-term toxicity in patients after cisplatin-based chemotherapy for non-seminomatous testicular cancer. Ann Oncol 2002;13(2):229-36. [Context Link]

44. Fossa SD. Long-term sequelae after cancer therapy--survivor-ship after treatment for testicular cancer. Acta Oncol 2004;43(2):134-41. [Context Link]

45. Rock E, DeMichele A. Nutritional approaches to late toxicities of adjuvant chemotherapy in breast cancer survivors. J Nutr 2003;133(11 Suppl 1):3785S-93S. [Context Link]

46. Armstrong T, et al. Chemotherapy-induced peripheral neuropathy. Oncol Nurs Forum 2005;32(2):305-11 [Context Link]

47. Cavaletti G, Zanna C. Current status and future prospects for the treatment of chemotherapy-induced peripheral neurotoxicity. Eur J Cancer 2002;38(14):1832-7. [Context Link]

48. Savarese DM, et al. Prevention of chemotherapy and radiation toxicity with glutamine. Cancer Treat Rev 2003;29(6):501-13. [Context Link]

49. Argyriou AA, et al. Vitamin E for prophylaxis against chemotherapy-induced neuropathy: a randomized controlled trial. Neurology 2005;64(1):26-31. [Context Link]

50. Cata JP, et al. Spinal cord stimulation relieves chemotherapy-induced pain: a clinical case report. J Pain Symptom Manage 2004;27(1):72-8. [Context Link]

51. Rauch P, et al. Quality of life among disease-free survivors of rectal cancer. J Clin Oncol 2004;22(2):354-60. [Context Link]

52. Panchal SJ, et al. Adult cancer pain. Jenkintown, PA: National Comprehensive Cancer Network; 2005. (Clinical practice guidelines in oncology, v.2.2005). http://www.nccn.org/professionals/physician_gls/PDF/pain.pdf. [Context Link]

53. Carr DB, et al. Evidence report on the treatment of pain in cancer patients. J Natl Cancer Inst Monogr 2004(32):23-31. [Context Link]

54. Dworkin RH, et al. Advances in neuropathic pain: diagnosis, mechanisms, and treatment recommendations. Arch Neurol 2003;60(11):1524-34. [Context Link]

55. Gordon DB, Love G. Pharmacologic management of neuropathic pain. Pain Manag Nurs 2004;5(4 Suppl 1):19-33. [Context Link]

56. Stacey BR. Management of peripheral neuropathic pain. Am J Phys Med Rehabil 2005;84(3 Suppl):S4-16. [Context Link]

57. Arnstein P. Chronic neuropathic pain: issues in patient education. Pain Manag Nurs 2004;5(4 Suppl 1):34-41. [Context Link]

58. Tesauro GM, et al. Survivorship resources for post-treatment cancer survivors. Cancer Pract 2002;10(6):277-83. [Context Link]

59. Almadrones L, et al. Psychometric evaluation of two scales assessing functional status and peripheral neuropathy associated with chemotherapy for ovarian cancer: a gynecologic oncology group study. Oncol Nurs Forum 2004;31(3):615-23. [Context Link]

60. Visovsky C, Daly BJ. Clinical evaluation and patterns of chemotherapy-induced peripheral neuropathy. J Am Acad Nurse Pract 2004;16(8):353-9. [Context Link]