#215 Opioid-Poorly Responsive Cancer Pain

FAST FACTS AND CONCEPTS #215

Opioid Poorly-Responsive Cancer Pain

Tamara Sacks MD, David E Weissman MD, and Robert Arnold MD

Background Relief of cancer pain from opioids is rarely all or nothing; most patients experience some degree of analgesia alongside opioid toxicities. When the balance of analgesia versus toxicity tips away from analgesia, the term ‘opioid poorly-responsive pain’ is invoked. While opioid poorly-responsive pain is not a discreet syndrome, it is a commonly encountered clinical scenario. This Fast Fact reviews key points in its assessment and management.

Differential Diagnosis of Opioid Poorly-Responsive Pain

1. Cancer-related pain

a. Cancer progression (new fracture at site of known bone metastases).

b. Causes of pain (eg. neuropathic pain, skin ulceration, rectal tenesmus, muscle pain) that are known to be less responsive to systemic opioids or opioid monotherapy.

c. Psychological/spiritual pain related to the cancer experience (existential pain of impending death).

2. Opioid pharmacology/technical problems

a. Opioid tolerance (rapid dose escalation with no analgesic effect).

b. Dose-limiting opioid toxicity (sedation, delirium, hyperalgesia, nausea – see Fast Facts #25, 142).

c. Poor oral absorption (for PO meds) or skin absorption (e.g. transdermal patch adhesive failure).

d. Pump, needle, or catheter problems (IV, subcutaneous, or spinal opioids).

3. Non-cancer pain

a. Worsening of a known non-cancer pain syndrome (diabetic neuropathy).

b. New non-cancer pain syndrome (dental abscess).

4. Other psychological problems

a. Depression, anxiety, somatization, hypochondria, factitious disorders.

b. Dementia and delirium both can effect a patient’s report of and experience of pain.

c. Opioid substance use disorders or opioid diversion.

Management Strategy

1. Initial Steps

a. Complete a thorough pain assessment including questions exploring psychological and spiritual concerns. If substance abuse or diversion is suspected, complete a substance abuse history (see Fast Facts #68, 69).

b. Complete a physical examination and order diagnostic studies as indicated.

c. Escalate a single opioid until acceptable analgesia or unacceptable toxicity develop, or it is clear that additional analgesic benefit is not being derived from dose escalation. If this fails, consider:

i. Rotating to a different opioid (e.g. morphine to methadone).

ii. Changing the route of administration (e.g. oral to subcutaneous).

d. Treat opioid toxicities aggressively.

e. Use (start or up-titrate) adjuvant analgesics, especially for neuropathic pain syndromes.

f. Integrate non-pharmacological treatments such as behavioral therapies, physical modalities like heat and cold, and music and other relaxation-based therapies – see Fast Fact #211.

2. Additional steps – Pain refractory to the initial steps requires multi-disciplinary input and care coordination.

a. Hospice/Palliative Medicine consultation to optimize pain assessment, drug management, and assessment of overall care goals.

b. Mental health consultation for help in diagnosis and management of suspected psychological factors contributing to pain.

c. Chaplain/Clergy assistance for suspected spiritual factors contributing to pain.

d. Interventional Pain and/or Radiation Oncology consultation.

e. Rehabilitation consultations (Physiatry, Physical and Occupational Therapy) to maximize physical analgesic modalities.

f. Pharmacist assistance with drug/route information.

References

1. Mercadante F, Portenoy RK. Opiate Poorly Responsive Cancer Pain Parts 1-3. J Pain Symptom Management. 2001; 21(2):144-150, 21(3):255-264, 24(4):338-354.

2. Smith TJ, Staats PS, Deer T, et al. Randomized clinical trial of an implantable drug delivery system compared with comprehensive medical management for refractory cancer pain: impact on pain, drug-related toxicity, and survival. J Clin Oncol. 2002; 20(19):4040-9.

3. Fallon M. When morphine does not work. Support Care Cancer. 2008; 16(7):771-5.

4. Quigley C. Opioid switching to improve pain relief and drug tolerability. Cochrane Database of Systematic Reviews. 2004, Issue 3. Art. No.: CD004847. DOI: 10.1002/14651858.CD004847.

5. Hanks GW. Opioid-responsive and opioid-non-responsive pain in cancer. Br Med Bull. 1991; 47(3):718-31.

6. Hanks G, Forbes K. Opioid responsiveness. Acta Anaesthesiologica Scand.1997; 41:154-158.

Author Affiliations: University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania (TS, RA), and Medical College of Wisconsin, Milwaukee, Wisconsin (DEW).

#214: Prognosis in HIV Associated Malignancies

FAST FACTS AND CONCEPTS #214

PROGNOSIS IN HIV ASSOCIATED MALIGNANCIES

Steven Oppenheim MD

Background Fast Fact #213 introduced prognostic principles in HIV/AIDS, as well as gave survival data for many life-threatening complications of HIV infection. This Fast Fact presents survival data for malignancies commonly arising in the setting of HIV/AIDS. Before applying these data to individual patients, consideration should be given to the prognostic principles in HIV/AIDS discussed in Fast Fact #213.

Prognostic Data

· AIDS related Kaposi’s sarcoma (KS), has become less common since the use of combination antiretroviral therapy (cART). It is a grossly violaeous spindle cell tumor, more common amongst men who have sex with men, and is associated with co-infection with human herpes virus-8. KS can involve the skin, mucous membranes, and viscera. Some patients with mild to moderate KS may have complete resolution of their disease with cART and/or chemotherapy. More extensive disease of the skin or viscera portends a poorer prognosis with a 2 year survival of 58%. A prognostic index has been developed for patients with KS on cART. In this index age > 50 years, developing KS as a later-stage complication of HIV infection (as opposed to KS being a patient’s first AIDS-defining illness), CD4 cell count <100 style=""> Patients with all 4 poor markers had a 1 year survival of ~40%.

· Primary CNS lymphoma is strongly associated with Epstein Barr virus infection. Treatments include cART, whole brain radiation and chemotherapy. Median survival was 3 months before the use of cART, but has improved to16 months for those responding to cART (with ≥ 50 CD4 cell count increase over their baseline count or ≥ 0.5log10* HIV viral load decrease after lymphoma diagnosis).

· Systemic non-Hodgkin’s Lymphoma (Diffuse Large Cell Lymphoma - DLCL) is the most common lymphoma associated with HIV infection. A decreased incidence has not been observed with cART, although survival in HIV patients is now approaching that of DLCL patients without HIV. 5 year survival with current chemotherapy regimens is approximately 50%. A well-validated tool for stratifying DLCL survival is the International Prognostic Index (IPI) which includes age, tumor stage, serum LDH, performance status, and number of extranodal disease sites. Patients with intermediate-risk IPI scores have a 50-64% 3 year survival. However patients with high-risk IPI scores have only a 13% 3 year survival, even in the cART era (see references 3, 9).

· Squamous cell carcinoma (SCC) of the cervix is seen frequently in patients with HIV and is caused by the human papilloma virus. Survival data are limited for HIV infected patients, but it appears to be similar to patients without HIV infection and is unaffected by the use of or response to cART. Five year survival of SCC of the cervix is 86% for locally invasive disease, 43% with regional disease, and 11% with metastatic disease.

· Squamous cell carcinoma (SCC) of the anus, while not officially an AIDS-defining malignancy, is 120 times more common in HIV infected than non-infected patients and is also associated with human papilloma virus infection. Survival does not seem to be affected by HIV status, with overall 2 year survival in the ~75% range.

* 0.5 log10 decrease equals, for instance, a decrease of 4.0 to 3.5 log10, or 10,000 to 3,160 copies HIV-RNA/ml.

References

1. Bernstein WB, Little RF, Wilson WH, Yarchoan R. Acquired Immunodeficiency Syndrome-related malignancies in the era of highly active antiretroviral therapy. Int. J Hematology. 2006; 84:3-11.

2. Biggar RJ, Engles EA, Ly S, et al. Survival after cancer diagnosis in persons with AIDS. JAIDS. 2005; 39:293-299.

3. Bower M, Gazzard B, Mandalia S, et al. A prognostic index for systemic AIDS-related non-Hodgkin lymphoma treated in the era of highly active antiretroviral therapy. Ann Intern Med. 2005; 143:265-273.

4. Cheung MC, Pantanowitz L, Dezube BJ. AIDS Related Malignancies: Emerging challenges in the era of highly active antiretroviral therapy. The Oncologist. 2005; 10:412-426.

5. Chiao EY, Giordano TP, Richardson P, El-Serag HB. Human Immunodeficiency Virus-associated squamous cell cancer of the anus: Epidemiology and outcomes in the highly active antiretroviral therpy era. J Clin Onc. 2008; 26:474-479.

6. Hentrich M, Maretta L, Chow KU, et al. Highly active antiretroviral therapy (HAART) improves survival in HIV-associated Hodgkin’s disease: results of a multicenter study. Ann Oncology. 2006; 17:914-919.

7. Hoffmann C, Tabrizian S, Wolf E. Survival of AIDS patients with primary central nervous system lymphoma is dramatically improved by HAART-induced immune recovery. AIDS. 2001; 15:2119-2127.

8. Goldie SJ, Weinstein MC, Kuntz KM, Freedberg KA. The costs, clinical benefits and cost-effectiveness of screening for cervical cancer in HIV-infected women. Ann Intern Med. 1999; 130:97-107.

9. Lim ST, Karim R, Tulpule A, Nathwani BN, Levine AM. Prognostic factors in HIV-related diffuse large-cell lymphoma: before versus after highly active antiretroviral therapy. J Clin Oncol. 2005; 23:8477-8482.

10. Mounier N, Spina M, Gisselbreght C. Modern management of non-Hodgkin lymphoma in HIV-infected patients. Br J Haem. 2007; 136:685-698.

11. Oehler-Janne C, Huguet F, Provencher S, et al. HIV specific differences in outcome of squamous cell carcinoma of the anal canal: a multicentric cohort study of HIV-positive patients receiving highly active antiretroviral therapy. J Clin Onc. 2008; 26:2550-2557.

12. Skiest DJ, Crosby C. Survival is prolonged by highly active antiretroviral therapy in AIDS patients with primary central nervous system lymphoma. AIDS. 2003; 17:1787-1793.

13. Stebbing J, Sanitt A, Nelson M, Gazzard B, Bower M. A prognostic index for AIDS-associated Kaposi’s sarcoma in the era of highly active antiretroviral therapy. Lancet. 2006; 367:1495-1502.

14. Uronis HE, Bendell JC. Anal cancer: an overview. The Oncologist. 2007; 12:524-534.

Author Affiliation: San Diego Hospice at the Institute for Palliative Care, San Diego, California.