lunes, 11 de marzo de 2019

Cancer Pain (PDQ®) 1/2 —Health Professional Version - National Cancer Institute

Cancer Pain (PDQ®)—Health Professional Version - National Cancer Institute

National Cancer Institute

Cancer Pain (PDQ®)–Health Professional Version

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General Information About Cancer Pain



Pain is one of the most common symptoms in cancer patients and often has a negative impact on patients’ functional status and quality of life. The goal of the following summary is to provide evidence-based, up-to-date, and practical information on the management of cancer pain.
Effective pain management can generally be accomplished by paying attention to the following steps:[1]
  1. Regular screening to ensure that the patient’s pain is recognized early. (Refer to the Pain Assessment section of this summary for more information.)
  2. Proper characterization of the pain to identify underlying pathophysiology, which could significantly influence treatment options. (Refer to the Pain Classificationsection of this summary for more information).
    • Is the pain acute or chronic?
    • Is it secondary to cancer, cancer treatment, other causes, or a combination?
    • Is it somatic, visceral, neuropathic, or mixed?
    • Is there an incidental component?
    • Is there breakthrough pain?
  3. Determining whether the pain requires pharmacologic and/or other modalities of treatment. Pain is often multifactorial in nature, so factors that may modulate pain expression, such as psychological distress and substance use, should be assessed. (Refer to the Background and Definitions section of this summary for more information.)
    • What is the impact of pain on the patient?
    • Is the benefit of treatment likely going to outweigh the risks?
  4. Identifying the optimal pharmacologic and nonpharmacologic treatment options (refer to the Pharmacologic Therapies for Pain Control section of this summary for more information), including referrals to specialists, if needed. (Refer to the Modalities for Pain Control: Other Approaches section of this summary for more information.) Complex pain often requires multidimensional interdisciplinary evaluation and intervention. There are many issues to consider when determining the most appropriate treatment, such as the following:
    • Previous pain treatments.
    • Patient prognosis.
    • Predictive factors for pain control (e.g., psychological distress).
    • Impact on function.
    • Comorbidities (e.g., renal or hepatic failure).
    • Risk of misuse of or addiction to pain medications.
    • Patient preference.
  5. Providing proper education about treatment, including medication administration, expected side effects and associated treatments, and when patients can expect improvement. If opioids are considered, opioid phobia and the risks of opioid use and misuse should be addressed. Patients and family caregivers should be educated about the safe storage, use, and disposal of opioids. One study demonstrated that improper use, storage, and disposal are common among cancer outpatients.[2]
  6. Monitoring the patient longitudinally with return visits to titrate/adjust treatments. Patients with cancer or noncancer pain requiring chronic therapy are monitored closely to optimize treatment and to minimize the likelihood of complications of opioid use, including misuse or abuse. The risks and benefits of opioid use are evaluated regularly, and physician impressions are discussed openly with the patient.

Background and Definitions

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.”[3] Pain is commonly experienced by cancer patients. Its proper assessment requires measuring pain intensity; clarifying the impact of pain on patients’ psychological, social, spiritual, and existential domains; and establishing treatment adherence and responsiveness.
A commonly used approach to pain management employs the World Health Organization (WHO) pain relief ladder, which categorizes pain intensity according to severity and recommends analgesic agents based on their strength.[4] Pain intensity is often assessed using a numeric rating scale (NRS) of 0 to 10. On this scale, 0 indicates no pain, 1 to 3 indicates mild pain, 4 to 6 indicates moderate pain, and 7 to 10 indicates severe pain.[5]
Step 1 on the WHO pain relief ladder treats mild pain. Patients in this category receive nonopioid analgesics such as acetaminophen, nonsteroidal anti-inflammatory drugs, or an adjuvant analgesic, if necessary. Step 2 treats patients experiencing mild to moderate pain who are already taking a nonopioid analgesic, with or without an adjuvant analgesic, but who are still experiencing poor analgesia. Step 2 agents include tramadol and acetaminophen products containing hydrocodone, oxycodone, and codeine. Step 3 treats moderate to severe pain with strong analgesics. Step 3 opioids include morphine, hydromorphone, fentanyl, levorphanol, methadone, oxymorphone, and oxycodone. An open-label randomized trial of low-dose morphine versus weak opioids to treat moderate cancer pain suggests that it is acceptable to bypass weak opioids and go directly to strong opioids (step 3 agents) for patients with moderate cancer pain, as patients randomly assigned to the low-dose morphine group had more frequent and greater reduction in pain intensity with similarly good tolerability and earlier effect.[6]
Familiarity with opioid pharmacokinetics, equianalgesic dosing, and adverse effects is necessary for their safe and effective use. The appropriate use of adjuvant pharmacological and nonpharmacological interventions is needed to optimize pain management.

Prevalence

Pain occurs in 20% to 50% of patients with cancer.[7] Roughly 80% of patients with advanced-stage cancer have moderate to severe pain.[8] One meta-analysis looking at pooled data from 52 studies found that more than half of patients had pain.[9] Younger patients are more likely to experience cancer pain and pain flares than are older patients.[10]
Cancer patients often have multiple sites of pain.[11] Patients rated pain from 4 to 6 (severe) on the NRS, with exacerbations rated as high as 7.

Causes of Cancer Pain: Cancer, Cancer Treatments, and Comorbidities

A study evaluating the characteristics of patients (N = 100) with advanced cancer presenting to a palliative care service found the primary tumor as the chief cause of pain in 68% of patients.[11] Most pain was somatic, and pain was as likely to be continuous as intermittent.
Pain can be caused by cancer therapies, including surgery, radiation therapy, chemotherapy, targeted therapy, supportive care therapies, and/or diagnostic procedures. A systematic review of the literature identified reports of pain occurring in 59% of patients receiving anticancer treatment and in 33% of patients after curative treatments.[9] The prevalence of chronic nonmalignant pain—such as chronic low back pain, osteoarthritis pain, fibromyalgia, and chronic daily headaches—has not been well characterized in cancer patients. It has been reported to be between 2% and 76%, depending on the patient population and how pain was assessed.[12-15]

Postoperative pain

Pain is an expected consequence of surgery. Concerns about the prevalence of opioid misuse have drawn increasing attention to how opioids are prescribed in common settings, including postoperatively. Studies suggest widespread variation in the prescribing patterns of opioids in the postoperative setting.[16] One study of opioid use after orthopedic and general surgery procedures found that, on average, only between 19% and 34% of the opioids prescribed were used and that the quantity of opioids prescribed after a given procedure varied widely by provider.[16] This finding led to the evaluation of utilization data and recommendations for standardizing the quantity of opioids prescribed for five common general surgery procedures.[17] An educational intervention based on those recommendations was associated with a 53% decrease in prescribed opioids after those five general surgery procedures, with only 1 patient in a cohort of 246 patients requiring an opioid refill.[18]
The opioid epidemic has also raised questions about whether postoperative use of opioids can lead to misuse. New persistent opioid use develops in 6% to 8% of opioid-naïve patients after noncancer surgery.[19-21] In a large retrospective analysis of patients undergoing curative-intent cancer surgery, 10.4% of opioid-naïve patients developed new persistent opioid use, defined as filling opioid prescriptions 90 to 180 days after surgery. At 1 year postsurgery, these patients were using an average of six 5-mg hydrocodone (or equivalent) tablets per day. Among the risk factors evaluated, only the use of adjuvant chemotherapy increased the risk of new persistent opioid use (15%–21% risk with adjuvant chemotherapy vs. 7%–11% risk with no chemotherapy).[22] In summary, one in ten patients undergoing curative-intent cancer surgery may be at risk of postoperative persistent opioid use.

Infusion-related pain syndromes

The infusion of intravenous chemotherapy causes four pain syndromes: venous spasm, chemical phlebitis, vesicant extravasation, and anthracycline-associated flare.[23-25] Venous spasm is treated by application of a warm compress or decrease in the infusion rate. Chemical phlebitis may result from chemotherapy or nonchemotherapy infusions such as potassium chloride and hyperosmolar solutions.[24] Vesicant extravasation may cause intense pain followed by desquamation and ulceration.[23] Doxorubicin may result in the venous flare reaction, which includes local urticaria, pain, or stinging.[25] Some chemotherapy agents such as vinorelbine may cause pain at the tumor site.[26]

Treatment-related mucositis

Severe mucositis often occurs as a consequence of myeloablative chemotherapy and standard-intensity therapy.[27] Cytotoxic agents commonly associated with mucositis are cytarabine, doxorubicin, etoposide, 5-fluorouracil, and methotrexate. Epidermal growth factor receptor (EGFR) inhibitors, multitargeted tyrosine kinase inhibitors, and mammalian target of rapamycin inhibitors also cause mucositis.[28,29] Risk factors for mucositis include preexisting oral pathology, poor dental hygiene, and younger age.[27]

Chemotherapy-related musculoskeletal pain

Paclitaxel generates a syndrome of diffuse arthralgias and myalgias in 10% to 20% of patients.[30] Diffuse pain in joints and muscles appears 1 to 2 days after the infusion and lasts a median of 4 to 5 days. Pain originates in the back, hips, shoulders, thighs, legs, and feet. Weight bearing, walking, or tactile contact exacerbates the pain. Steroids may reduce the tendency to develop myalgia and arthralgias. Among hormonal therapies, aromatase inhibitors cause musculoskeletal symptoms, osteoporotic fractures, arthralgias, and myalgias.[31]

Dermatologic complications and chemotherapy

EGFR inhibitors cause dermatitis with ensuing pain.[32] Acute herpetic neuralgia occurs with a significantly increased incidence among cancer patients, especially those with hematologic malignancies and those receiving immunosuppressive therapies.[33] The pain usually resolves within 2 months but can persist and become postherpetic neuralgia. The palmar-plantar erythrodysesthesia syndrome is observed in association with continuously infused 5-fluorouracil, capecitabine,[34] liposomal doxorubicin,[35] and paclitaxel.[36] Targeted agents such as sorafenib and sunitinib are also associated with hand-foot–like syndrome.[37] Patients develop tingling or burning in their palms and soles, followed by an erythematous rash. Management often requires discontinuing therapy or reducing the treatment dose.

Supportive care therapies and pain

Supportive care therapies can cause pain, as typified by bisphosphonate-associated osteonecrosis of the jaw.[38] Corticosteroid use has also been associated with the development of avascular necrosis.[39]

Radiation-induced pain

Radiation is associated with several distinct pain syndromes. First, patients may experience pain from brachytherapy and from positioning during treatment (i.e., placement on a radiation treatment table). Second, delayed tissue damage such as mucositis, mucosal inflammation in areas receiving radiation, and dermatitis may be painful. Third, a temporary worsening of pain in the treated area (a pain flare) is a potential side effect of radiation treatment for bone metastases.[40] A randomized trial demonstrated that dexamethasone (8 mg on day of radiation therapy and daily for the following 4 days) reduces the incidence of pain flares, compared with placebo.[41] (Refer to the External-Beam Radiation Therapy section of this summary for more information.)

Impact on Function and Quality of Life

Cancer pain is associated with increased emotional distress. Both pain duration and pain severity correlate with risk of developing depression. Cancer patients are disabled an average of 12 to 20 days per month, with 28% to 55% unable to work because of their cancer.[42] Cancer survivors may experience distress when their pain unexpectedly persists after completion of cancer treatments.[43] Survivors also experience loss of support from their previous health care team as oncologists transition their care back to primary care providers.
In one study, between 20% and 50% of cancer patients continued to experience pain and functional limitations years posttreatment.[44] Untreated pain leads to requests for physician-assisted suicide.[45] Untreated pain also leads to unnecessary hospital admissions and visits to emergency departments.[46]

References
  1. Hui D, Bruera E: A personalized approach to assessing and managing pain in patients with cancer. J Clin Oncol 32 (16): 1640-6, 2014. [PUBMED Abstract]
  2. Reddy A, de la Cruz M, Rodriguez EM, et al.: Patterns of storage, use, and disposal of opioids among cancer outpatients. Oncologist 19 (7): 780-5, 2014. [PUBMED Abstract]
  3. Merskey H, Bogduk N, eds.: Classification of Chronic Pain: Descriptions of Chronic Pain Syndromes and Definitions of Pain Terms. 2nd ed. Seattle, Wash: IASP Press, 1994. Also available online. Last accessed September 10, 2018.
  4. Davis MP, Walsh D: Epidemiology of cancer pain and factors influencing poor pain control. Am J Hosp Palliat Care 21 (2): 137-42, 2004 Mar-Apr. [PUBMED Abstract]
  5. Oldenmenger WH, de Raaf PJ, de Klerk C, et al.: Cut points on 0-10 numeric rating scales for symptoms included in the Edmonton Symptom Assessment Scale in cancer patients: a systematic review. J Pain Symptom Manage 45 (6): 1083-93, 2013. [PUBMED Abstract]
  6. Bandieri E, Romero M, Ripamonti CI, et al.: Randomized Trial of Low-Dose Morphine Versus Weak Opioids in Moderate Cancer Pain. J Clin Oncol 34 (5): 436-42, 2016. [PUBMED Abstract]
  7. Fischer DJ, Villines D, Kim YO, et al.: Anxiety, depression, and pain: differences by primary cancer. Support Care Cancer 18 (7): 801-10, 2010. [PUBMED Abstract]
  8. Bruera E, Kim HN: Cancer pain. JAMA 290 (18): 2476-9, 2003. [PUBMED Abstract]
  9. van den Beuken-van Everdingen MH, de Rijke JM, Kessels AG, et al.: Prevalence of pain in patients with cancer: a systematic review of the past 40 years. Ann Oncol 18 (9): 1437-49, 2007. [PUBMED Abstract]
  10. Green CR, Hart-Johnson T: Cancer pain: an age-based analysis. Pain Med 11 (10): 1525-36, 2010. [PUBMED Abstract]
  11. Gutgsell T, Walsh D, Zhukovsky DS, et al.: A prospective study of the pathophysiology and clinical characteristics of pain in a palliative medicine population. Am J Hosp Palliat Care 20 (2): 140-8, 2003 Mar-Apr. [PUBMED Abstract]
  12. 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 82 (3): 263-74, 1999. [PUBMED Abstract]
  13. Barbera L, Molloy S, Earle CC: Frequency of non-cancer-related pain in patients with cancer. J Clin Oncol 31 (22): 2837, 2013. [PUBMED Abstract]
  14. Childers JW, King LA, Arnold RM: Chronic Pain and Risk Factors for Opioid Misuse in a Palliative Care Clinic. Am J Hosp Palliat Care 32 (6): 654-9, 2015. [PUBMED Abstract]
  15. Massaccesi M, Deodato F, Caravatta L, et al.: Incidence and management of noncancer pain in cancer patients referred to a radiotherapy center. Clin J Pain 29 (11): 944-7, 2013. [PUBMED Abstract]
  16. Kim N, Matzon JL, Abboudi J, et al.: A Prospective Evaluation of Opioid Utilization After Upper-Extremity Surgical Procedures: Identifying Consumption Patterns and Determining Prescribing Guidelines. J Bone Joint Surg Am 98 (20): e89, 2016. [PUBMED Abstract]
  17. Hill MV, McMahon ML, Stucke RS, et al.: Wide Variation and Excessive Dosage of Opioid Prescriptions for Common General Surgical Procedures. Ann Surg 265 (4): 709-714, 2017. [PUBMED Abstract]
  18. Hill MV, Stucke RS, McMahon ML, et al.: An Educational Intervention Decreases Opioid Prescribing After General Surgical Operations. Ann Surg 267 (3): 468-472, 2018. [PUBMED Abstract]
  19. Clarke H, Soneji N, Ko DT, et al.: Rates and risk factors for prolonged opioid use after major surgery: population based cohort study. BMJ 348: g1251, 2014. [PUBMED Abstract]
  20. Soneji N, Clarke HA, Ko DT, et al.: Risks of Developing Persistent Opioid Use After Major Surgery. JAMA Surg 151 (11): 1083-1084, 2016. [PUBMED Abstract]
  21. Brummett CM, Waljee JF, Goesling J, et al.: New Persistent Opioid Use After Minor and Major Surgical Procedures in US Adults. JAMA Surg 152 (6): e170504, 2017. [PUBMED Abstract]
  22. Lee JS, Hu HM, Edelman AL, et al.: New Persistent Opioid Use Among Patients With Cancer After Curative-Intent Surgery. J Clin Oncol 35 (36): 4042-4049, 2017. [PUBMED Abstract]
  23. Sauerland C, Engelking C, Wickham R, et al.: Vesicant extravasation part I: Mechanisms, pathogenesis, and nursing care to reduce risk. Oncol Nurs Forum 33 (6): 1134-41, 2006. [PUBMED Abstract]
  24. Pucino F, Danielson BD, Carlson JD, et al.: Patient tolerance to intravenous potassium chloride with and without lidocaine. Drug Intell Clin Pharm 22 (9): 676-9, 1988. [PUBMED Abstract]
  25. Curran CF, Luce JK, Page JA: Doxorubicin-associated flare reactions. Oncol Nurs Forum 17 (3): 387-9, 1990 May-Jun. [PUBMED Abstract]
  26. Long TD, Twillman RK, Cathers-Schiffman TA, et al.: Treatment of vinorelbine-associated tumor pain. Am J Clin Oncol 24 (4): 414-5, 2001. [PUBMED Abstract]
  27. Peterson DE, Lalla RV: Oral mucositis: the new paradigms. Curr Opin Oncol 22 (4): 318-22, 2010. [PUBMED Abstract]
  28. Lacouture ME, Anadkat MJ, Bensadoun RJ, et al.: Clinical practice guidelines for the prevention and treatment of EGFR inhibitor-associated dermatologic toxicities. Support Care Cancer 19 (8): 1079-95, 2011. [PUBMED Abstract]
  29. Boers-Doets CB, Epstein JB, Raber-Durlacher JE, et al.: Oral adverse events associated with tyrosine kinase and mammalian target of rapamycin inhibitors in renal cell carcinoma: a structured literature review. Oncologist 17 (1): 135-44, 2012. [PUBMED Abstract]
  30. Loprinzi CL, Maddocks-Christianson K, Wolf SL, et al.: The Paclitaxel acute pain syndrome: sensitization of nociceptors as the putative mechanism. Cancer J 13 (6): 399-403, 2007 Nov-Dec. [PUBMED Abstract]
  31. Coleman RE, Bolten WW, Lansdown M, et al.: Aromatase inhibitor-induced arthralgia: clinical experience and treatment recommendations. Cancer Treat Rev 34 (3): 275-82, 2008. [PUBMED Abstract]
  32. Lynch TJ Jr, Kim ES, Eaby B, et al.: Epidermal growth factor receptor inhibitor-associated cutaneous toxicities: an evolving paradigm in clinical management. Oncologist 12 (5): 610-21, 2007. [PUBMED Abstract]
  33. Portenoy RK, Duma C, Foley KM: Acute herpetic and postherpetic neuralgia: clinical review and current management. Ann Neurol 20 (6): 651-64, 1986. [PUBMED Abstract]
  34. Gressett SM, Stanford BL, Hardwicke F: Management of hand-foot syndrome induced by capecitabine. J Oncol Pharm Pract 12 (3): 131-41, 2006. [PUBMED Abstract]
  35. Alberts DS, Garcia DJ: Safety aspects of pegylated liposomal doxorubicin in patients with cancer. Drugs 54 (Suppl 4): 30-5, 1997. [PUBMED Abstract]
  36. Vukelja SJ, Baker WJ, Burris HA 3rd, et al.: Pyridoxine therapy for palmar-plantar erythrodysesthesia associated with taxotere. J Natl Cancer Inst 85 (17): 1432-3, 1993. [PUBMED Abstract]
  37. Chu D, Lacouture ME, Fillos T, et al.: Risk of hand-foot skin reaction with sorafenib: a systematic review and meta-analysis. Acta Oncol 47 (2): 176-86, 2008. [PUBMED Abstract]
  38. Prommer EE: Toxicity of bisphosphonates. J Palliat Med 12 (11): 1061-5, 2009. [PUBMED Abstract]
  39. Mattano LA Jr, Devidas M, Nachman JB, et al.: Effect of alternate-week versus continuous dexamethasone scheduling on the risk of osteonecrosis in paediatric patients with acute lymphoblastic leukaemia: results from the CCG-1961 randomised cohort trial. Lancet Oncol 13 (9): 906-15, 2012. [PUBMED Abstract]
  40. Ripamonti CI, Bossi P, Santini D, et al.: Pain related to cancer treatments and diagnostic procedures: a no man's land? Ann Oncol 25 (6): 1097-106, 2014. [PUBMED Abstract]
  41. Chow E, Meyer RM, Ding K, et al.: Dexamethasone in the prophylaxis of radiation-induced pain flare after palliative radiotherapy for bone metastases: a double-blind, randomised placebo-controlled, phase 3 trial. Lancet Oncol 16 (15): 1463-72, 2015. [PUBMED Abstract]
  42. Brown LF, Kroenke K, Theobald DE, et al.: The association of depression and anxiety with health-related quality of life in cancer patients with depression and/or pain. Psychooncology 19 (7): 734-41, 2010. [PUBMED Abstract]
  43. Jim HS, Andersen BL: Meaning in life mediates the relationship between social and physical functioning and distress in cancer survivors. Br J Health Psychol 12 (Pt 3): 363-81, 2007. [PUBMED Abstract]
  44. Harrington CB, Hansen JA, Moskowitz M, et al.: It's not over when it's over: long-term symptoms in cancer survivors--a systematic review. Int J Psychiatry Med 40 (2): 163-81, 2010. [PUBMED Abstract]
  45. Foley KM: The relationship of pain and symptom management to patient requests for physician-assisted suicide. J Pain Symptom Manage 6 (5): 289-97, 1991. [PUBMED Abstract]
  46. Mayer DK, Travers D, Wyss A, et al.: Why do patients with cancer visit emergency departments? Results of a 2008 population study in North Carolina. J Clin Oncol 29 (19): 2683-8, 2011. [PUBMED Abstract]

Pain Classification


Total Pain

The concept of total pain captures its multidimensional nature by explicitly including the physical, psychological, social, and spiritual components of pain.[1-4] The immediate implications for the clinician are severalfold:
  1. A complete assessment of pain requires screening for psychological distress, social disruption, and existential crises, to treat the pain effectively and to anticipate barriers to pain relief.
  2. Patients’ descriptions of pain that seem out of proportion to the known pathology may reflect other syndromes such as depression and existential distress.[5]
  3. Patients suffering from pain often require multidimensional interventions from supportive services such as palliative care, chaplaincy, or psychotherapy.[6]
  4. The concept of total pain does not suggest that pain is solely caused by psychological or existential distress, but that psychological and spiritual components can exacerbate or ameliorate the experience of pain. If the clinician suspects somatization, then referral for psychiatric or psychological evaluation is indicated.

Pain Mechanisms

Pain is classified on the basis of the underlying pathophysiologic mechanisms, the duration, or the description of recognizable syndromes associated with pain.[7] The three mechanisms underlying the pathophysiology of pain are nociceptive, neuropathic, and psychogenic.
Nociceptive pain, which may be either somatic or visceral in nature, originates with a chemical, mechanical, or thermal injury to tissue that stimulates pain receptors that transmit a signal to the central nervous system (CNS), causing the perception of pain. Pain receptors are found in somatic (e.g., cutaneous, bone) and visceral tissues. The amount of visceral sensory innervation and the diffusion of visceral pain signals within the brain explain the difficulty experienced by patients in describing or localizing visceral pain compared with somatic pain. A specific type of visceral pain is referred pain, which is explained by the commingling of nerve fibers from somatic and visceral nociceptors at the level of the spinal cord. Patients mistakenly interpret the pain as originating from the innervated somatic tissue. Visceral pain may be accompanied by autonomic signs such as sweating, pallor, or bradycardia. Somatic pain is more easily localized.
Neuropathic pain is pain caused by damage to the peripheral nervous system or the CNS (spinal cord or brain). Causes of neuropathic pain of particular relevance to cancer include chemotherapy (e.g., vinca alkaloids), infiltration of the nerve roots by tumor, or damage to nerve roots (radiculopathy) or groups of nerve roots (plexopathy) due to tumor masses or treatment complications (e.g., radiation plexopathy).[8] The pain may be evoked by stimuli or spontaneous. Patients who experience pain from nonnoxious stimuli are classified as having allodynia. Hyperalgesia connotes increased sensations of pain out of proportion to what is usually experienced.
Emotional distress may also contribute to the pain experience. Most patients with cancer and pain do not have somatic symptom disorder. However, if pain complaints appear to be disproportionate to the underlying pain stimulus, it is important to evaluate for psychological and existential distress contributing to the pain complaint, chemical coping, and substance abuse.

Acute and Chronic Cancer Pain

Pain is often classified as either acute or chronic or by how it varies over time with terms such as breakthrough, persistent, or incidental. Acute pain is typically induced by tissue injury, begins suddenly with the injury, and diminishes over time with tissue healing. There is no definite length but, in general, acute pain resolves within 3 to 6 months.[9] The treatment of acute pain focuses on blocking nociceptive pathways while the tissue heals.
Chronic pain typically persists even after the injury has healed, although patients with chronic joint disease, for example, may have ongoing tissue damage and therefore experience chronic pain. Pain becomes chronic when it continues for more than 1 month after the healing of precipitating lesions; persists or becomes recurrent over months; or results from lesions unlikely to regress or heal.[9] The transition from acute to chronic pain may be understood as a series of relatively discrete changes in the CNS,[9] but there are also clearly behavioral confounders in the genesis of chronic pain. Chronic pain involves the activation of secondary mechanisms such as the sensitization of second-order neurons by upregulation of N-methyl-D-aspartic acid channels and alteration in microglia cytoarchitecture. Chronic pain, with its multiple factors for perpetuation, often benefits from a multidisciplinary approach to treatment.

Breakthrough Pain

In caring for patients with pain, breakthrough pain is distinguished from background pain.[10,11] Breakthrough pain is a transitory increase or flare of pain in the setting of relatively well-controlled acute or chronic pain.[12] Incident pain is a type of breakthrough pain related to certain often-defined activities or factors such as movement increasing vertebral body pain from metastatic disease. It is often difficult to treat such pain effectively because of its episodic nature.[13] In one study, 75% of patients experienced breakthrough pain; 30% of this pain was incidental, 26% was nonincidental, 16% was caused by end-of-dose failure, and the rest had mixed etiologies.[14]

References
  1. Richmond C: Dame Cicely Saunders. Br Med J 331 (7510): 238, 2005. Also available online. Last accessed September 10, 2018.
  2. Mehta A, Chan LS: Understanding of the concept of “total pain”: a prerequisite for pain control. J Hosp Palliat Nurs 10 (1): 26-32, 2008.
  3. Syrjala KL, Jensen MP, Mendoza ME, et al.: Psychological and behavioral approaches to cancer pain management. J Clin Oncol 32 (16): 1703-11, 2014. [PUBMED Abstract]
  4. Merskey H, Bogduk N, eds.: Classification of Chronic Pain: Descriptions of Chronic Pain Syndromes and Definitions of Pain Terms. 2nd ed. Seattle, Wash: IASP Press, 1994. Also available online. Last accessed September 10, 2018.
  5. Porter LS, Keefe FJ: Psychosocial issues in cancer pain. Curr Pain Headache Rep 15 (4): 263-70, 2011. [PUBMED Abstract]
  6. Wachholtz A, Makowski S: Spiritual dimensions of pain and suffering. In: Moore RJ, ed.: Handbook of Pain and Palliative Care: Biobehavioral Approaches for the Life Course. New York, NY: Springer, 2013, pp 697-713.
  7. Chang VT, Janjan N, Jain S, et al.: Update in cancer pain syndromes. J Palliat Med 9 (6): 1414-34, 2006. [PUBMED Abstract]
  8. Dworkin RH, Backonja M, Rowbotham MC, et al.: Advances in neuropathic pain: diagnosis, mechanisms, and treatment recommendations. Arch Neurol 60 (11): 1524-34, 2003. [PUBMED Abstract]
  9. Voscopoulos C, Lema M: When does acute pain become chronic? Br J Anaesth 105 (Suppl 1): i69-85, 2010. [PUBMED Abstract]
  10. Portenoy RK, Hagen NA: Breakthrough pain: definition, prevalence and characteristics. Pain 41 (3): 273-81, 1990. [PUBMED Abstract]
  11. Narayana A, Katz N, Shillington AC, et al.: National Breakthrough Pain Study: prevalence, characteristics, and associations with health outcomes. Pain 156 (2): 252-9, 2015. [PUBMED Abstract]
  12. Caraceni A, Martini C, Zecca E, et al.: Breakthrough pain characteristics and syndromes in patients with cancer pain. An international survey. Palliat Med 18 (3): 177-83, 2004. [PUBMED Abstract]
  13. Mercadante S: Managing difficult pain conditions in the cancer patient. Curr Pain Headache Rep 18 (2): 395, 2014. [PUBMED Abstract]
  14. Gutgsell T, Walsh D, Zhukovsky DS, et al.: A prospective study of the pathophysiology and clinical characteristics of pain in a palliative medicine population. Am J Hosp Palliat Care 20 (2): 140-8, 2003 Mar-Apr. [PUBMED Abstract]

Pain Assessment


Patient-Reported Outcomes

Effective pain treatment begins with screening at every visit and a thorough assessment if pain is present. Patient self-report is the standard of care for evaluating pain.[1]
Many tools have been developed to quantify the intensity of pain. The most commonly used tools include the numerical rating scale (0–10: 0 = no pain, 10 = worst pain imaginable); the categorical scale (none, mild, moderate, severe); and the visual analog scale (0–100 mm: 0 mm = no pain, 100 mm = worst pain imaginable). Multidimensional pain assessment tools such as the McGill Pain Questionnaire, the Brief Pain Inventory,[2] and the PROMIS-PI (Patient-Reported Outcomes Measurement Information System—Pain Interference) [3] have been developed to evaluate pain and its interference with daily functions. Although these tools are important, they may be best applied in the research setting, given their complexity and significant time requirements.
Pain assessment tools have been developed for special populations such as children and those with cognitive impairment (refer to the Special Considerations section of this summary for more information).
Pain intensity may be assessed for different time frames, such as “now,” “last 24 hours,” or “last week.” In addition to the average pain intensity, the worst or lowest intensity may be assessed. Evaluation of pain intensity at each visit would allow clinicians to monitor for changes and treatment response. Pain intensity scales can also be used to develop a personalized pain goal.[4]

Clinician Assessment

Failure to assess pain adequately leads to undertreatment. Assessment involves both clinician observation and patient report. The goal of the initial pain assessment is to characterize the pathophysiology of the pain and to determine the intensity of the pain and its impact on the patient’s ability to function. It is important to recognize that psychosocial issues can either exacerbate or ameliorate the experience of pain.[5] These psychosocial issues cannot be easily treated through pharmacologic approaches; therefore, it is critical that clinicians include these in initial and subsequent examinations of patients with pain to ensure referrals to appropriate treatment resources. Furthermore, distinct cultural components may need to be incorporated into a multidimensional assessment of pain, including how culture influences the pain experience, pain communication, and provider response to pain expression.[6-9]
Identifying the etiology of pain is important to its management. Clinicians treating patients with cancer need to recognize the common cancer pain syndromes. (Refer to the Approach to Somatic Pain, Approach to Visceral Pain, and Approach to Neuropathic Pain sections of this summary for more information.)
Effective pain management requires close monitoring of patient response after treatment is initiated. In a review of 1,612 patients referred to an outpatient palliative care center, more than half of patients with moderate to severe pain did not show pain relief (a reduction in 2 out of 10 points or a 30% decrease on the pain scale) after the initial palliative care consultation.[10] In addition, one-third of patients with mild pain progressed to moderate to severe pain by the time of their first follow-up visit. The study also identified baseline pain intensity, fatigue, and Edmonton Symptom Assessment System symptom burden as factors predicting response.[10]
Ideally, comprehensive pain assessment includes a discussion about the patient’s goals and expectations for pain management. This conversation may lead to a fruitful discussion about balancing pain levels and other patient goals, such as mental alertness. Comprehensive pain assessment also includes pain history, pain intensity, quality of pain, and location of pain. For each pain location, the pattern of pain radiation is assessed. Also important is provider awareness of the patient’s current pain management treatment plan and how the patient has responded to treatment; this includes how adequately the current treatment plan addresses any breakthrough or episodic pain. A full assessment also reviews previously attempted pain therapies and reasons for discontinuation; other associated symptoms such as sleep difficulties, fatigue, depression, and anxiety; functional impairment; and any relevant laboratory data and diagnostic imaging. A focused physical examination includes clinical observation of pain behaviors, pain location, and functional limitations.
Psychosocial and existential factors that can affect pain are also assessed and appropriately treated. Depression and anxiety can have a large influence on the pain experience. Across many different types of pain, research has shown the importance of considering a patient’s sense of self-efficacy over their pain: low self-efficacy, or focus on solely pharmacologic solutions, is likely to increase the use of pain medication.[11,12] In addition, patients who repeatedly catastrophize pain (e.g., patient reports pain higher than 10 on a 10-point scale) are more likely to require higher doses than are patients who do not catastrophize. Catastrophizing is strongly associated with low self-efficacy and reliance on chemical coping strategies.[13-17] Furthermore, assessing the impact of pain on the individual’s life and associated factors that exacerbate or relieve pain can reveal how psychosocial issues are affecting the patient’s pain levels.
A pain assessment includes a review of any patient and family history of substance use and the extent of the patient’s chemical coping strategies before and since the cancer diagnosis. The extent of chemical coping strategies, including reliance on legal substances (e.g., nicotine, alcohol, and sleeping pills), may indicate a history of reliance on chemicals to alleviate distress. It can also provide the clinician with information about the patient’s nicotine use, which may affect how certain opioids may be differentially metabolized and the amount of opioids required to achieve pain control.[18] A remote history of substance abuse can still affect current pain levels and analgesic requirements. Remote substance use may have long-term implications for pain sensitivity, even if the patient has a history of prolonged abstinence from opioid use.[19] Together, personal and family substance use can inform a risk assessment for potential abuse of medications, potential analgesic requirements, and diversion of prescriptions.

Pain Prognostic Scores

A number of pain-related factors and patient-related factors predict response to pain treatment. Specifically, a high baseline pain intensity, neuropathic pain, and incident pain are often more difficult to manage.[20] Furthermore, several patient characteristics such as a personal or family history of illicit drug use, alcoholism ,[21,22] smoking,[23-25] somatization,[26] mental health issues such as depression or anxiety,[27] and cognitive dysfunction [28-30] are associated with higher pain expression, higher opioid doses, and longer time to achieve pain control.
On the basis of these predictive factors, several risk scores have been developed to assist clinicians in clinical practice, such as the Edmonton Classification System for Cancer Pain (ECS-CP) [20,31] and the Cancer Pain Prognostic Scale (CPPS).[32]
  • The ECS-CP consists of (1) neuropathic pain, (2) incident pain, (3) psychological distress, (4) addiction, and (5) cognitive impairment. The presence of any of these factors indicates that pain may be more difficult to control. The ECS-CP has been validated in various cancer pain settings.[33]
  • The CPPS includes four variables in a formula to determine the risk score, including worst pain severity (Brief Pain Inventory), Functional Assessment of Cancer Therapy - General (FACT-G) emotional well-being, initial morphine equivalent daily dose (≤60 mg/day; >60 mg/day), and mixed pain syndrome. The CPPS score ranges from 0 to 17, with a higher score indicating a higher possibility of pain relief.
Predictive factors can help to personalize cancer pain management. Especially for patients with a poor pain prognosis, clinicians may consider discussing realistic goals for alleviating pain, focusing on function and use of multimodality interventions. Repeated or frequent escalation of analgesic doses without improvement of pain may trigger clinicians to consider an alternative approach to pain.

Special Considerations

Self-report is accepted as the gold standard of pain assessment; however, for certain vulnerable populations, such as children, those with learning disabilities, and those who are cognitively impaired, self-report may not be feasible or reliable.
While adults and children older than 7 years can effectively utilize the numerical rating scale, young children and those with cognitive impairment may benefit from using a pictorial scale such as the Faces Pain Scale.[34] (Refer to the PDQ summary on Pediatric Supportive Care for more information.)
Cognitive impairment may impede a person’s ability to describe pain, recall pain events, or understand the tools used to assess pain, leading such patients to receive more or less analgesia.[35-37] The American Society for Pain Management Nursing has developed a position statement on pain assessment in the nonverbal patient that includes clinical recommendations.[38] Pain assessment can be evaluated via direct observation, family/caregiver report, and evaluation of response to pain relief interventions. For patients with advanced dementia, tools relying on professional caregiver assessment of pain through the observation of patient behaviors have been developed.[39-41] Although the validity and reliability of these tools have been questioned, the tools are often recommended for patients with advanced dementia who cannot report pain and, in combination with self-report by other cognitively impaired groups, as a means to enhance pain assessment and avoid undertreatment of pain.
Cognitive impairment extends beyond patients with a diagnosis of dementia, such as those with brain tumors and delirium, which are common complications of advanced cancer. In such patients, the Faces Pain Scale [42] and the Coloured Analogue Scale [43] as well as vertical instead of horizontal orientation of scales may be preferable to the numeric rating scales.[44]
Culture also plays a role in the patient experience of pain and the reporting of pain. For example, among some Asian cultures, patients tend not to report pain.[6] Complaining of pain may be perceived as a sign of weakness. Individuals may hide pain from family members to avoid burdening the family. For some patients, pain may have spiritual value, leading them to accept pain rather than dull the experience with medication.[45] Thus, understanding an individual patient’s spiritual and cultural background without making assumptions is important in approaching pain assessment.
In a cross-sectional study, the cancer pain experience of white patients was individual and independent, while that of ethnic minority patients was family oriented. Minority patients received support from their families during the cancer treatment, and they fought cancer for their families. The families were involved deeply in their decision making related to cancer treatment and pain management.[7]
Other studies indicate that Asian patients have greater barriers to pain management and display more fatalism than do Western patients.[8,9]

References
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  38. Herr K, Coyne PJ, Key T, et al.: Pain assessment in the nonverbal patient: position statement with clinical practice recommendations. Pain Manag Nurs 7 (2): 44-52, 2006. [PUBMED Abstract]
  39. Warden V, Hurley AC, Volicer L: Development and psychometric evaluation of the Pain Assessment in Advanced Dementia (PAINAD) scale. J Am Med Dir Assoc 4 (1): 9-15, 2003 Jan-Feb. [PUBMED Abstract]
  40. Fuchs-Lacelle S, Hadjistavropoulos T: Development and preliminary validation of the pain assessment checklist for seniors with limited ability to communicate (PACSLAC). Pain Manag Nurs 5 (1): 37-49, 2004. [PUBMED Abstract]
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  43. McGrath PA, Seifert CE, Speechley KN, et al.: A new analogue scale for assessing children's pain: an initial validation study. Pain 64 (3): 435-43, 1996. [PUBMED Abstract]
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  45. Ferrell B: Ethical perspectives on pain and suffering. Pain Manag Nurs 6 (3): 83-90, 2005. [PUBMED Abstract]

Pharmacologic Therapies for Pain Control


Acetaminophen and Nonsteroidal Anti-inflammatory Drugs (NSAIDs)

Often initiated when an individual has mild pain, acetaminophen and NSAIDs are useful in managing moderate and severe pain as adjunct agents to opioids. No single NSAID is preferred over others, and all are better than placebo for analgesia.[1] As opioid adjuncts, acetaminophen and NSAIDs have shown benefit both in improved analgesia and in decreased opioid use. These agents are used with care or perhaps avoided in patients who are elderly or have renal, hepatic, or cardiac disease.[1] (Refer to the Geriatric cancer patients section in the Treatment of Pain in Specific Patient Populations section of this summary for more information.)
While acetaminophen and NSAIDs provide analgesia on their own, a number of randomized controlled trials have reported that the addition of either agent to opioids may improve pain control and decrease opioid need in cancer patients.[2-4] However, these benefits were not consistently observed across trials.[5,6]
High-potency NSAIDs such as ketorolac and diclofenac are more studied and have shown benefit in the management of cancer pain, but there are no comparative data with older agents to show superiority of one product over others. Prominent side effects are gastrointestinal irritation, ulcer formation, and dyspepsia, with other side effects of concern being cardiotoxicity, nephrotoxicity, hepatotoxicity, and hematologic effects.[7,8] Cyclooxygenase-2 (COX-2)–specific agents such as celecoxib may have a more favorable gastrointestinal side effect profile at a higher monetary cost.[7] Long-term safety and efficacy data remain unclear.
Table 1. Acetaminophen and Selected Nonsteroidal Anti-inflammatory Analgesics
DrugDosageCommentsReference(s)
COX-2 = cyclooxygenase-2; GI = gastrointestinal; IM = intramuscular; IV = intravenous; NSAIDs = nonsteroidal anti-inflammatory drugs; PO = by mouth.
Acetaminophen<4,000 mg/dDosed every 4 to 8 hours, depending on dose and product used.[2]
Celecoxib200–400 mg/dCOX-2 specific. Minimal antiplatelet effects compared with nonselective NSAIDs.[7]
Diclofenac100–200 mg/dAvailable as immediate- and delayed/extended–release products.[9]
Ibuprofen600–2,400 mg/d[9]
Ketoprofen100–300 mg/dAvailable as parenteral in some parts of the world, which may be preferred.[7,10]
Ketorolac40–60 mg/d, generally dosed every 6 hoursParenteral (IV, IM) ketorolac is used ≤5 days because of concerns about GI adverse events. May also be given PO.[7]

Opioids

General principles

The use of opioids for the relief of moderate to severe cancer pain is considered necessary for most patients.[1] For moderate pain, weak opioids (e.g., codeine or tramadol) or lower doses of strong opioids (e.g., morphine, oxycodone, or hydromorphone) are often administered and frequently combined with nonopioid analgesics. For severe pain, strong opioids are routinely used; although no agent has shown itself to be more effective than another, morphine is often considered the opioid of choice because of provider familiarity, broad availability, and lower cost.[1] In one well-designed review, most individuals with moderate to severe cancer pain obtained significant pain relief from oral morphine.[11] One study has also noted that low-dose morphine (up to 30 mg orally per day) provided better analgesia than did weak opioids (codeine, tramadol).[12]
Management of acute pain begins with an immediate-release opioid formulation. Once pain is stabilized, the opioid consumption over the past 24 hours is then converted to a modified-release or longer-acting opioid on the basis of the patient’s 24-hour opioid consumption (measured in terms of morphine equivalent daily dose [MEDD]). Randomized controlled trials have shown that long-acting opioids given every 12 hours provide efficacy similar to that of scheduled short-acting opioids given every 4 hours.[13,14] Use of the immediate-release product is continued for management of breakthrough pain.[1] During ongoing pain management, the immediate-release opioids inform the titration of long-acting medication. Rapid-acting oral, buccal, sublingual, transmucosal, rectal, and intranasal products are all acceptable for treatment of breakthrough pain. In people unable to take oral medications, a subcutaneous method of delivery is as effective as the intravenous route for morphine and hydromorphone.
Table 2. Selected Opioid Analgesics
Opioid DrugEquianalgesic DosingCommentsReference(s)
BuprenorphineNo consensusTransdermal product and sublingual available. May cause less constipation and nausea than do other opioids.[15-17]
Codeine100 mgMaximum of 360 mg/d. Used with or without acetaminophen.[1,18]
DiamorphineUnavailableUsed primarily in the United Kingdom.[19]
Fentanyl7.5 µg/h × 24 h ~ 15 mg oral morphine/dayDelivered transdermally, transmucosally, or intravenously. Cachectic patients have decreased absorption from transdermal patch.[18,20,21]
Hydrocodone10 mgGenerally used with acetaminophen, for moderate pain only.[22]
Hydromorphone3 mg[10]
Methadone3 mg (equianalgesic ratio varies widely by dose)Used primarily for severe pain in non–opioid-naïve patients. Unusual pharmacokinetics require experienced practitioner.[1]
Morphine15 mgRandomized trials supporting use. First-choice opioid because of familiarity, availability, and cost.[1,18]
Oxycodone10 mgRandomized trials supporting use.[18]
Oxymorphone5 mg[10]
Tapentadol75 mgSimilar to morphine 40–100 mg.[23]; [24][Level of evidence: I]
Tramadol150 mgUse at <400 mg/d with or without acetaminophen. Used for moderate pain.[1]
Table 3. Routes of Analgesic Medication Administration
RouteAgentCommentsReference(s)
NSAIDs = nonsteroidal anti-inflammatory drugs.
BuccalFentanylUsed primarily for breakthrough pain.[25]
EpiduralOpioids, local anestheticsConsider if inadequate analgesia or intolerable side effects with oral or intravenous analgesics.[1]
Intramuscular injectionOpioids, acetaminophen, ketorolacTypically avoided because of pain from injection.[10]
IntranasalFentanylOnset faster than that of transmucosal fentanyl or oral morphine. Used for breakthrough pain.[25]
IntrathecalOpioidsConsider if inadequate analgesia or intolerable side effects with oral or intravenous analgesics.[1]
IntravenousMost strong opioids (except oxycodone) and some NSAIDsAvailability varies by world region.[10]
OralMost opioids except fentanyl and buprenorphineMost common and preferred method of administration.[10]
RectalMorphine, methadoneOnset similar to that of oral; possibly better absorption. May be useful for pediatric and end-of-life patients.[1]
SubcutaneousMorphine, diamorphine, fentanyl, hydromorphone, ketoprofen, methadoneBenefit similar to that of intravenous; considered an alternative if no oral capacity.[1,2,26]
SublingualFentanyl, buprenorphineUsed primarily for breakthrough pain.[16,25]
TopicalLidocainePrimarily application of topical anesthetics.[10]
TransdermalFentanyl, buprenorphineEfficacy similar to that of oral agents for moderate to severe pain in opioid-naïve patients.[1]
TransmucosalFentanylUsed primarily for breakthrough pain.[25]

Rapid-onset fentanyl formulations

Rapid-onset opioids are developed to provide fast analgesia without using a parenteral route. Fentanyl, a synthetic opioid 50 to 100 times more potent than morphine, is available in a variety of delivery methods to offer additional options for management of breakthrough pain.[27] Along with rapid onset of action, these products avoid first-pass hepatic metabolism and intestinal digestion.
All rapid-acting fentanyl products are intended for use only in patients already tolerant to opioids and are not initiated in the opioid naïve. However, none are bioequivalent to others, making dose interchange complicated and requiring dose titration of each product individually, without regard to previous doses of another fentanyl product. The dose titration schedule is unique to each product, and it is critical that product information is reviewed individually when each product is used. The risk of addiction with these rapid-onset agents has not been elucidated. In the United States, prescription of these agents requires enrollment in the U.S. Food and Drug Administration’s (FDA’s) Risk Evaluation and Mitigation Strategies (REMS) program.
Table 4. Routes of Fentanyl Administration
DrugStarting Dose (µg)Tmax(median, minutes)CommentsEvidence
DB = double blinded; PC = placebo controlled; RCT = randomized controlled trial; Tmax = time to maximum blood concentration.
Transmucosal fentanyl lozenges (Actiq, generic)20020–40Lozenge on stick, rubbed against cheek. Sugar content may increase dental caries.Multiple RCTs showing benefit over placebo and oral morphine.
Fentanyl buccal tablet (Fentora)100, 200, or 40035–45Absorption may be affected by mucositis. Before use, wet mouth if dry.RCT showing benefit over placebo, and open-label study showing benefit for pain rescue; more rapid than oxycodone.
Fentanyl buccal film (Onsolis)20060Before use, wet mouth if dry.DB, PC, RCT showing benefit.
Fentanyl nasal spray (Lazanda)10015–21Vial contains residual fentanyl when empty, requiring special disposal. Do not use with decongestant sprays.DB, PC, RCT showed benefit. Open-label RCT showed benefit over transmucosal fentanyl and oral morphine.
Fentanyl sublingual spray (Subsys)10040–75Contains residual fentanyl when empty, requiring special disposal.Open-label and PC RCT showing benefit.
Fentanyl sublingual tablet (Abstral)10030–60Absorption may be affected by mucositis. Before use, wet mouth if dry.Multiple PC RCTs showing benefit.

Methadone

Methadone is both a mu-receptor agonist and an N-methyl-D-aspartate (NMDA) receptor antagonist; can be given via multiple routes (oral, intravenous, subcutaneous, and rectal); has a long half-life (13 to 58 hours) and rapid onset of action; and is inexpensive, making it an attractive option for cancer pain control. Because of its NMDA properties, methadone may be particularly useful for the management of opioid-induced neurotoxicity, hyperalgesia, and neuropathic pain, although further studies are needed to confirm these theoretical benefits. Methadone is safer for patients with renal failure, and is preferred for those with known opioid allergies because it is a synthetic opioid. However, methadone also has several distinct disadvantages, including drug interactions, the risk of QT prolongation, and a variable equianalgesic ratio, making rotation more challenging.
Given the complexities related to methadone administration, it is important that this opioid be prescribed by clinicians with experience who are able to provide careful monitoring. Referral to a pain specialist or a palliative care team may be indicated.
Methadone is metabolized by CYP3A4 and CYP2D6. CYP3A4 inducers (e.g., certain anticonvulsants and antiretroviral agents) can potentially reduce its analgesic effect.[28] In contrast, substrates/inhibitors of CYP3A4 may increase methadone’s activity, including side effects. For clinicians, the potential for significant drug-drug interactions may mean that some medications need to be replaced and that patients need extra monitoring. Furthermore, because methadone is a substrate of P-glycoprotein, medications that inhibit the activity of this transporter, such as verapamil and quinidine, may increase methadone’s bioavailability.
Methadone is associated with QT prolongation. This risk increases in patients receiving high doses (especially >100 mg/day) or with preexisting risk factors, including treatment with some anticancer agents. For patients with risk factors for QT prolongation, it is important to conduct a baseline electrocardiogram (ECG) before treatment with methadone. A follow-up ECG is recommended at 2 to 4 weeks after methadone initiation if the patient has known risk factors, with the occurrence of new risk factor(s) for all patients, and when the doses of methadone reach 30 to 40 mg/day and 100 mg/day for all patients regardless of risk.[29]
One group of investigators reported that the conversion ratio for switching from oral morphine to methadone varied between 2.5 and 14.3, with greater potency as the MEDD increased.[30] In a small retrospective study, other investigators found that the equianalgesic ratio for switching from methadone to oral morphine was 4.7 for oral methadone and 13.5 for intravenous methadone.[31]
A systematic review has highlighted three approaches to methadone conversion in the literature;[32,33] however, the evidence was low, making it difficult to conclude which approach was superior. Rapid titration of methadone may result in delayed respiratory depression because of its long half-life.[34]

Adverse effects

Adverse effects from opioids are common and may interfere with achieving adequate pain control. However, not all adverse effects are caused by opioids, and other etiologies also need to be evaluated. Examples of relevant factors include symptoms from disease progression, comorbid health conditions, drug interactions (including adjuvant analgesics), and clinical conditions such as dehydration or malnutrition.[35] In general, options for addressing adverse effects associated with opioids include aggressive management of the adverse effects, opioid rotation, or dose reduction. In most instances, definitive recommendations are not possible.
Table 5. Relative Prevalence of Opioid Adverse Effects by Duration of Usea
Adverse EffectRelative PrevalencebComments
Acute UsecChronic Used
aThe reported prevalence may differ on the basis of opioid choice, dose, route, and duration of use.
bRelative prevalence: (–) absent; (+) rare; (++) less common; (+++) common.
cAcute use defined as use for ≤2 weeks, as-needed use, and upon significant dose increase.
dChronic use defined as consistent use for >2–3 months at stable doses.
Cardiovascular
Hypotension++Mostly with intravenous opioids.
Central nervous system
Sedation++++More common upon opioid initiation and dose increase.[36]
Dizziness+++[10]
Delirium/hallucinations++[10]
Impaired cognitive status+++[10]
Sleep disturbances+++[10]
Gastrointestinal
Nausea++++Slow upward dose titration reduces risk. Lower rates with hydromorphone vs. morphine.[36,37]
Vomiting+++[10]
Constipation++++++[38]
Autonomic nervous system
Xerostomia++++[10]
Bladder dysfunction/urinary retention++[10]
Respiratory
Respiratory depression+–Extremely rare if used appropriately.[36]
Dermatologic
Pruritus++–More common with spinal analgesia.[36]
Miscellaneous
Hyperalgesia–+Observed more commonly with opioid-induced neurotoxicity. May be more common with morphine and hydromorphone.[39]
Opioid endocrinopathy/hypogonadism–+[40,41]
Hypoglycemia++May be observed among patients on tramadol or methadone. More common among diabetics.
Central nervous system (CNS) effects
Adverse effects on the CNS may be attributed to opioids’ anticholinergic activity or direct effect on neurons.[42,43] Sedation and drowsiness are common but typically transient adverse effects. Patients who have persistent problems may benefit from opioid rotation. Methylphenidate has been proposed as an intervention to reduce opioid-induced sedation.[44,45] The effects of opioids on cognitive or psychomotor functioning are not well established. Given the incidence of sedation, caution is exercised when an opioid is initiated or when dose escalation is required. There is less evidence, however, that patients on chronic stable doses exhibit cognitive or motor impairment.[46]
Delirium is associated with opioids but is typically multifactorial in origin.[47] In one retrospective study, 80% of the delirium cases were not related to opioids.[48] (Refer to the Delirium section in the PDQ summary on Last Days of Life for more information about the management of delirium.)
Respiratory depression
Opioid-induced respiratory depression may be caused by a blunting of the chemoreceptive response to carbon dioxide and oxygen levels and altered mechanical function of the lung necessary for efficient ventilation and gas exchange.[49] Opioid-induced respiratory depression may manifest through decreased respiratory rate, hypoxemia, or increases in total exhaled carbon dioxide.[50] The prevalence of respiratory depression is not known but rarely occurs with proper opioid use and titration.[51-54]
If respiratory depression is thought to be related to opioids (e.g., in conjunction with pinpoint pupils and sedation), naloxone, a nonselective competitive opioid antagonist, may be useful; however, careful titration should be considered because it may compromise pain control, and may precipitate withdrawal in opioid-dependent individuals. Because of methadone’s long half-life, naloxone infusion may be required for respiratory depression caused by methadone.
Nausea and vomiting
Opioid-induced nausea occurs in up to two-thirds of patients receiving opioids, and half of those patients will experience vomiting.[55] Opioids cause nausea and vomiting via enhanced vestibular sensitivity, via direct effects on the chemoreceptor trigger zone, and by causing delayed gastric emptying.[56] Antiemetics may be started up front in patients at risk of developing nausea, or instituted once symptoms occur. Tolerance to opioid-induced nausea and vomiting (OINV) may develop, and symptoms should resolve within 1 week. If symptoms persist despite treatment with antiemetics, opioid rotation can be considered, or other causes of nausea can be investigated.
OINV is treated with many of the same antiemetic drugs that are used for chemotherapy-induced nausea and vomiting. Although many antiemetic regimens have been proposed for OINV, there is no current standard.[56] The chemoreceptor trigger zone is stimulated by dopamine, serotonin, and histamine. Metoclopramide may be a particularly attractive option because of its dual antiemetic and prokinetic effects. Other dopamine antagonists such as prochlorperazine, promethazine, and olanzapine have been used to treat OINV. For patients whose nausea worsens with positional changes, a scopolamine patch has been found effective. Serotonin antagonists such as ondansetron may be used; however, they could worsen constipation among patients already taking opioids.
Constipation
Constipation is the most common adverse effect of opioid treatment, occurring in 40% to 95% of patients.[57] It can develop after a single dose of morphine, and patients generally do not develop tolerance to opioid-induced constipation. Chronic constipation can result in hemorrhoid formation, rectal pain, bowel obstruction, and fecal impaction.
Opioids cause constipation by decreasing peristalsis, which occurs by reducing gastric secretions and relaxing longitudinal muscle contractions, and results in dry, hardened stool.[58] Constipation is exacerbated by dehydration, inactivity, and comorbid conditions such as spinal cord compression. Patients are encouraged to maintain adequate hydration, fiber intake, and regular exercise, in addition to taking laxatives.
A scheduled stimulant laxative is started with opioid initiation. The addition of a stool softener offers no further benefit.[59,60] Laxatives are titrated to a goal of one unforced bowel movement every 1 to 2 days. If constipation persists despite prophylactic measures, then additional assessment of the cause and severity of constipation is performed. After obstruction and impaction are ruled out, other causes of constipation (such as hypercalcemia) are treated.
There is no evidence to recommend one laxative class over another in this setting. Appropriate drugs include bisacodyl, polyethylene glycol, magnesium hydroxide, lactulose, sorbitol, and magnesium citrate. Suppositories are generally avoided in the setting of neutropenia or thrombocytopenia.
Methylnaltrexone and naloxegol are peripherally acting opioid antagonists approved for the treatment of opioid-induced constipation in patients who have had inadequate response to conventional laxative regimens. Laxatives are discontinued before peripherally acting opioid antagonists are initiated. These agents are not used if postoperative ileus or mechanical bowel obstruction is suspected.[61,62]
Hyperalgesia
Defined as “the need for increasingly high levels of opioids to maintain pain inhibition after repeated drug exposure,” opioid-induced hyperalgesia (OIH) is a clinical phenomenon that has been differentiated from opioid tolerance in the research literature.[39,63-66]
The clinical relevance needs to be further studied, and this issue may be underappreciated in clinical practice.
A thorough history and physical are appropriate if OIH is suspected. Changes in pain perception and increasing opioid requirements may be caused by OIH, opioid tolerance, or disease progression. There is no standard recommendation for the diagnosis and treatment of OIH. A trial of incremental opioid dose reductions may lead to an improvement in pain from OIH. However, this may be psychologically distressing to oncology patients who require opioid treatment. Opioid rotation is a strategy frequently employed if opioid tolerance has occurred. Methadone is an ideal opioid to switch to, given its mechanism of action as an opioid receptor agonist and NMDA receptor antagonist. Given the similarities between OIH and neuropathic pain, the addition of an adjunctive medication such as pregabalin has been recommended.[39]
Opioid endocrinopathy
Opioid endocrinopathy (OE) is the effect of opioids on the hypothalamic-pituitary-adrenal axis and the hypothalamic-pituitary-gonadal axis over the long term. Opioids act on opioid receptors in the hypothalamus, decreasing the release of gonadotropin-releasing hormone.[67] This results in a decreased release of luteinizing hormone and follicle-stimulating hormone, and finally a reduction of testosterone and estradiol released from the gonads. These effects occur in both men and women.[41] Patients may present with symptoms of hypogonadism such as decreased libido, erectile dysfunction, amenorrhea or irregular menses, galactorrhea, depression, and hot flashes.
Treatment for OE is not well established. One group of investigators performed a 24-week, open-label pilot study of a testosterone patch in 23 men with opioid-induced androgen deficiency and reported an improvement in androgen deficiency symptoms, sexual function, mood, depression, and hematocrit levels.[68] There was no change in opioid use. Men and women with OE may be offered hormone replacement therapy after a thorough risk-benefit discussion. Testosterone replacement is contraindicated in men with prostate cancer; estrogen replacement therapy may be contraindicated in patients with breast and ovarian cancer and has serious associated health risks.
Opioid-induced immunological changes
Opioids have immunomodulatory effects through neuroendocrine mechanisms and by direct effects on opioid receptors on immune cells.[69] Opioids can alter the development, differentiation, and function of immune cells, causing immunosuppression.[40] Different opioids cause varying effects on the immune system. In mouse and rat models, methadone is less immunosuppressive than morphine. In contrast, tramadol improves natural killer cell activity. Further research is needed to determine the true clinical significance of opioid-induced immunosuppression, such as the risk of infections.

Opioid rotation

Opioid rotation or switching may be needed when one of the following occurs:[70,71]
  • The patient is experiencing side effects beyond what can be managed with simple measures. For example, the presence of opioid-induced neurotoxicity (e.g., myoclonus, hallucinations, vivid dreams, hyperalgesia, or delirium) almost always warrants opioid rotation.
  • Pain control remains suboptimal despite an active effort to titrate the opioid dose. Ideally, the opioid is increased to the highest tolerable level for the patient before switching occurs, to avoid abandoning an opioid prematurely.
  • A switch is needed for logistical reasons, such as change of the route of administration (e.g., from intravenous to oral in preparation for discharge or from oral to transdermal due to severe odynophagia); the need to minimize toxicities with the onset of renal/hepatic failure (e.g., from morphine to fentanyl or methadone); and cost considerations (e.g., long-acting oxycodone to methadone).
The selection of a target opioid depends on the reason for rotation. All strong opioids have similar efficacy and side effect profiles at equianalgesic doses. Because of the lack of predictors for specific opioids, empiric trials are needed to identify the ideal opioid. If opioid-induced neurotoxicity is the reason for switching, it may not matter which opioid is switched to, as long as it is a different agent. Importantly, patient preference, history of opioid use, route of administration, and cost are necessary considerations before the final choice is made.
A study of opioid rotation in the outpatient palliative care setting revealed that approximately one-third of 385 consecutive patients needed an opioid rotation, mostly for uncontrolled pain (83%) and opioid-induced neurotoxicity (12%).[72] The success rate was 65%, with a median pain improvement of two points out of ten (minimal clinically important difference is one point).[73]

Barriers related to opioid use

The barriers to appropriate use of opioids in the treatment of cancer pain include misunderstandings or misapprehensions about opioids by health care providers, patients, and society. One group of investigators surveyed 93 patients with cancer cared for in an academic practice in Australia to understand patient-level barriers to the use of opioids.[74] One-third of the patients reported high levels of pain that adversely affected activity, mood, sleep, and enjoyment of life. High percentages of patients reported concerns about addiction (76%) or side-effects (67%). In addition, patients expressed concerns that the pain represented disease progression (71%), that they were distracting the doctor (49%), or that they would not be seen as a “good patient” (46%).[74] Patients with more severe pain were more likely to express concerns about side effects and were less likely to use unconventional approaches to pain control. Results were similar to those of a survey of American patients from the previous decade.[75]
Physician-perceived barriers to opioid prescribing tend to parallel those of the patient.[76] Physicians and other health care providers have beliefs about addiction, for example, that inhibit prescribing. In addition, there are significant knowledge deficits that lead to inadequate dosing of opioids and unaddressed side effects.
Other barriers to opioid prescribing and compliance are the costs of abuse and misuse of opioids, which are estimated to be in the tens of billions of dollars and include increased mortality rates.[77] As a consequence, many states have developed prescription drug monitoring programs, and the FDA requires REMS for certain opioids (such as rapid-onset fentanyl products), which could serve as an additional barrier to opioid prescribing. Other barriers include poor or limited formulary and reimbursement for opioids.

Liver disease

The liver plays a major role in the metabolism and pharmacokinetics of opioids and most drugs. The liver produces enzymes involved in two forms of metabolism: phase 1 metabolism (modification reactions, CYP) and phase 2 metabolism (conjugation reactions, glucuronidation).[28]
Methadone and fentanyl are unaffected by liver disease and are drugs of choice in patients with hepatic failure.[78,79]
Morphine, oxymorphone, and hydromorphone undergo glucuronidation exclusively. CYP2D6 metabolizes codeine, hydrocodone, and oxycodone; CYP3A4 and CYP2D6 metabolize methadone; and CYP3A4 metabolizes fentanyl.[28] Hepatic impairment affects both CYP enzymes and glucuronidation processes. Prescribing information recommends caution when prescribing opioids for patients with hepatic impairment.
In cirrhosis, the elimination half-life and peak concentrations of morphine are increased.[80] Moderate to severe liver disease increases peak levels and the area under the curve (AUC) for both oxycodone and its chief metabolite, noroxycodone.[81] Peak plasma concentrations and AUC of another active metabolite, oxymorphone, are decreased by 30% and 40%, respectively.[81]
Although oxymorphone itself does not undergo CYP-mediated metabolism, a portion of the oxycodone dose is metabolized to oxymorphone by CYP2D6. Failure to convert oxycodone to oxymorphone may result in accumulation of oxycodone and noroxycodone, with an associated increase in adverse events. Hepatic disease increases the bioavailability of oxymorphone as liver function worsens.[82]

Renal insufficiency

Renal insufficiency affects the excretion of morphine, oxycodone, hydromorphone, oxymorphone, and hydrocodone. Methadone and fentanyl are safe to use in patients with renal failure, although there is some evidence that the hepatic extraction of fentanyl is affected by uremia.[83]
When patients with renal insufficiency receive hydromorphone and morphine, both hydromorphone and morphine metabolites accumulate, with the potential to cause neuro-excitatory adverse effects. Morphine, which has a higher risk of drug and metabolite accumulation, may be used in patients with mild renal failure but requires dosing at less-frequent intervals or at a lower daily dose to provide benefit with adequate safety.[81] In patients with stage III to stage IV chronic kidney disease (glomerular filtration rate <59 cc/min), morphine may not be desirable.[81]
There are conflicting reports about the safety of hydromorphone in patients with renal failure. One case series suggests adverse effects increasing when hydromorphone is given by continuous infusion to patients with renal failure.[84] Other series suggest that it is safe to use.[85] Although renal impairment affects oxycodone more than it does morphine, there is no critical accumulation of an active metabolite that produces adverse events.[81]

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