The use of opioids in the treatment of oncologic pain in the elderly

Silva, Ledismar José da; Mendanha, Diego Machado; Gomes, Patrícia Pádua

doi:10.5935/2595-0118.20200014

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REVIEW ARTICLE • BrJP 3 (1) • Jan-Mar 2020 • https://doi.org/10.5935/2595-0118.20200014 linkcopy

The use of opioids in the treatment of oncologic pain in the elderly

Authorship SCIMAGO INSTITUTIONS RANKINGS

BACKGROUND AND OBJECTIVES: The use of opioids in cancer is already widespread and proven by several well-controlled clinical trials. However, the elderly with cancer pain are=un-dertreated due to the lack of knowledge in the management of these patients, the underestimation of pain, as well as the fear of complications arising in this age group. Therefore, the scientific community contributes to giving inputs to create possible clinical and health guidelines. The present study aimed to perform a systematic literature review of opioid treatments proposed for cancer-related pain in elderly patients.

CONTENTS: The search on the literature included papers addressing cancer pain treatment with opioids among the elderly, published from 2008 to 2018, and available in Portuguese or English. Searches were conducted on Medical Literature, Analysis, and Retrieval System Online (MEDLINE) and Latin American and Caribbean Health Sciences Literature (LILACS) electronic databases using the keywords “cancer pain”, “opioids”, and “elderly” in both languages, combined with the Boolean operator “AND”. To analyze the quality of the method, the adapted Critical Appraisal Skills Programme was used. Of a total of 411 studies found, 32 were included. About 75% of the selected articles were published in the last five years.

CONCLUSION: The results showed that opioids remain the pillar to treat cancer-related pain in the elderly. They can be used for better management of pain, but with caution due to the possible adverse effects. In addition, pain management in the elderly requires a multifactorial analysis, including comorbidities, polypharmacy, and patient functionality. Therefore, an individualized approach in the elderly patient is required in order to enhance results, reduce side effects, and improve quality of life.

Keywords:
Cancer pain; Elderly; Opioids

Authors	Purpose	Methodology	Therapy	Conclusion
Passik¹³	Assess long-term opioid therapy, including unmet needs, risks, and solutions	Literature review	Opioids	Chronic pain and abuse of prescribed opioids are common and substantially affect patients, doctors, and the society. Aggressive treatment of chronic pain should be balanced with the need to minimize the risks of opioid abuse, misuse, and deviation.
Wilson et al.¹¹	Examine the prevalence of pain, its perceived severity, and its correlation across a range of physical, social, psychological, and existential symptoms.	Multicenter study addressing cancer patients' pain and assessing 21 other symptoms and concerns		Continued pain is a problem for many cancer patients under palliative care, especially in younger individuals approaching death
Paice and Ferrell⁸	Review available pain management treatments considering the individual needs of patients as well as special populations, including the elderly, cancer survivors, patients with addictive diseases, and those at the end of life.			The urgent need to address cancer pain issues emerged in oncology in the 1970s, largely influenced by the introduction of palliative care (PC). PC providers demonstrated that pain could be relieved, and failure to do so meant the decreased quality of life. Over the past 30 years, cancer pain relief has become a priority in oncology. Despite significant advances, there are still continuing barriers to quality of care and pain relief. There are many resources to assist doctors in treating cancer pain.
Rangel and Telles⁵	Address the principles for cancer pain treatment, as well as barriers related to patients, health professionals, and the health system.	Literature review		All physicians should be familiar with the use of analgesics. Opioids should not be prescribed just because the patient has a fatal disease, but according to the intensity of his/her pain.
Hennemann- Krause¹⁴	Present the rational use of analgesic drugs, highlighting their indications, doses, adverse effects, and proper care for the adequate prescription of common analgesics and opioids for the control of chronic cancer pain.	Literature review	Common analgesic drugs and opioids	Opioids prescription should not be done because the patient has a fatal disease, but according to the intensity of the pain.
Madadi et al.¹⁵	Identify patterns and characteristics among opioid users	Qualitative study	Opioids	New susceptible groups of opioid users with related cause of death were identified. The first evidence to help quantify the contribution of opioid misuse to user mortality in Canada
Srisawang et al.¹⁶	Assess the knowledge and attitudes of physicians and policymakers/regulators regarding the use of opioids for cancer pain management.	Cross-sectional study	Opioids	Continued education for physicians and conference organization is required for policymakers/regulators. Special education and training should be addressed to clarify the terms of physical addiction.
Zeppetella¹⁷	Known non-parenteral opioid formulations, such as sublingual fentanyl, which can provide faster and more effective relief from transitory exacerbation cancer pain.	Systematic review	Non-parenteral opioids, such as sublingual fentanyl	Fentanyl formulation available at doses of 100, 200, 400, 600 and 800 µg approved for the treatment of transitory exacerbation pain in opioid therapy tolerant adult cancer patients for underlying persistent cancer pain
Kraychete, Siqueira and Garcia¹⁸	Discuss recommendations for opioid use in newborns, children and the elderly	Systematic review	Opioids	The use of opioids at extreme ages is still a challenge. However, continued education around the subject is needed, stimulating clinical research and the creation of evidence-based recommendations. The safe use of these agents in the correct indication and proportion for pain relief decreases risks and should be the basis of sound clinical conduct.
Nunes, Garcia and Sakata¹⁹	Assess the use of morphine as the first drug for moderate cancer pain treatment in patients with advanced disease and/or metastasis, as an option to the recommendations of the WHO-recommended analgesic ladder.	Randomized controlled study	Morphine	The use of morphine as the first drug for pain treatment did not promote a better analgesic effect than the WHO-recommended ladder, and there was a higher incidence of adverse effects.
Rocha et al.²⁰	Analyze the self-care of older people living with cancer in outpatient treatment, from the perspective of their autonomy	Qualitative and descriptive research		The autonomy for self-care of the elderly is manifested in the concern with food, knowledge of the body's limits, changes imposed by living with cancer, and family support.
Kim et al.²¹	Assess pain response to opioid rotation or opioid combination in patients with uncontrolled cancer pain	Randomized study	Opioids	For patients with chronic uncontrolled cancer pain, both opioid rotation and combination strategies appear to provide significant pain relief and better patient satisfaction.
Reticena, Beuter and Sales²²	Understand the experiences of the elderly with cancer pain	Qualitative research based on Heidegger's phenomenology, with recorded interviews		Cancer pain has biopsychosocial repercussions for the elderly, generating changes in their life activities and requiring holistic and authentic care.
Reyes-Gibby, Anderson and Todd⁶	Determine the risk of opioid misuse among emergency services for cancer pain patients and assess the demographic and clinical factors associated with increased risk of opioid abuse.	A cross-sectional study with a convenience sample	Opioids	The risk of opioid misuse among cancer patients is substantial. Tracking misuse in emergency departments is feasible
Coluzzi et al.¹⁰	Review some basic principles of opioid analgesia based on experience and knowledge of current publications on this care	Literature review	Opioids	Establish titration, individualization, and gradual reduction, along with the application of other good medical practice and clinical experience/judgment, including non-pharmacological approaches, can assist health care professionals in the effort to achieve optimal pain treatment.
Galicia-Castillo¹²	Manage chronic pain safely in the elderly	Literature review		A complete assessment, including description and management of pain, comorbidities, physical examination, and diagnostic tests are required for patient control. It is also important to inquire about the history of substance abuse.
Cella et al.²³	Assess the prevalence of pain and opiophobia in cancer patients.	A cross-sectional study with patients undergoing exclusive cancer clinical treatment in an outpatient cancer hospital	Opioids	A high prevalence of moderate to severe pain was found in the observed patients, as well as a high prevalence of opiophobia.
Lin et al.²⁴	Examine Taiwan's opioid prescribing standards for cancer patients to discover their potential concerns	Review of claims in the Taiwan National Health Insurance database for cancer-diagnosed patients from 2003 to 2011	Opioids	The use of strong short-acting opioids increased during the study period. Instead of oral opioids, transdermal fentanyl was the most commonly used opioid among cancer patients in Taiwan.
Oosten et al.²⁵	Study the pharmacokinetics of subcutaneous and transdermal fentanyl and assess relays between subcutaneous and transdermal uses	Cohort study	Subcutaneous and transdermal fentanyl	Absorption may lead to fluctuations in plasma transdermal and subcutaneous fentanyl concentrations. Relay schemes are not applicable for subcutaneous and transdermal fentanyl rotations
Reddy et al.²⁶	Determine the relationship between the equivalent daily dose of morphine and the dose of transdermal fentanyl in opioid rotation	Retrospective study	Morphine and transdermal fentanyl	The median rotation rate of transdermal fentanyl for the equivalent daily morphine dose was 100 mg/day and 2.4 µg/h, suggesting that 100 µg/h is equivalent to the 240 mg daily morphine dose.
Barbera et al.²⁷	Verify whether opioid prescriptions changed among older adults after 2007, in the context of changing opioid regulations, and whether effects were different among patients with a history of cance	Elderly patients stratified annually into three groups: no history of cancer, diagnosed with cancer for more than 5 years and diagnosed with cancer for 5 years or less. Trends over time have been assessed per year for 1) opioid prescription rate, comparing trends before and after 2007; 2) average daily dose of opioid	Opioids	Decreasing prescription rates have been observed in some drug subclasses. The potential impact of these changes on the quality of symptom control for cancer patients requires further investigation.
Bennett, Paice and Wallace²⁸	Understand the comprehensive management of cancer pain, including a thorough assessment, along with the use of pharmacological, non-pharmacological, integrative, and interventional therapies.	Literature review	Pharmacological, non-pharmacological, integrative, and interventional therapies	Although cancer pain remains prevalent, it remains undertreated, partly due to the concerns about opioid use. Opioids' efficacy in advanced disease is already clearly established; however, there are still issues about opioids' safety and efficacy in long-term cancer survivors.
Haider et al.²⁹	Assess changes in the opioid type and prescription dose among patients who are referred by oncologists to an outpatient palliative care clinic	Review of electronic patient health records at new CP Outpatient Consultations between January 1 and April 30 of each year from 2010 to 2015. Demographic data, cancer type, and stage, symptom assessment, performance status, opioid data were collected. Opioid type and dose defined as the equivalent daily dose of morphine	Opioids	Over the past few years, the equivalent daily dose of morphine prescribed by reference oncologists has decreased. Following hydrocodone reclassification, the use of tramadol with less stringent prescription limit increased
Kuip et al.³⁰	Summarize the multiple factors studied that potentially influence fentanyl pharmacokinetics focusing on implications for cancer patients	Systematic review	Fentanyl	Although aging may influence the fentanyl pharmacokinetics, sound conclusions are difficult to draw. There is at least a risk of lower clearance and, therefore, greater accumulation in elderly patients. Therefore, fentanyl should be titrated with caution in elderly patients.
Lee et al.³¹	Assess the non-inferiority of oxycodone/naloxone compared to controlled-release oxycodone for cancer pain control	Randomized, open, phase IV, parallel-group clinical trial	Oxycodone/naloxone and oxycodone	The group receiving oxycodone/naloxone was no lower than the one receiving oxycodone in terms of pain reduction after 4 weeks of treatment and had a similar safety profile.
Nosek et al.³²	Compare analgesia and adverse effects during oral administration of morphine and oxycodone, transdermal fentanyl and buprenorphine in cancer and pain patients	Randomized clinical trial	Morphine, oxycodone, transdermal fentanyl, and buprenorphine	All opioids were effective and well-tolerated. Morphine was the most effective for pain improvement compared to some of the questionnaire items regarding the negative impact of pain on patients' daily activities.
Schmidt-Hansen et al.³³	Assess the efficacy and tolerability of oxycodone in any pain administration route in adults with cancer.	Systematic literature review	Oxycodone	For clinical purposes, oxycodone or morphine may be used as first-line oral opioids for pain relief in cancer adults.
Yen et al.⁷	Assess the efficacy and safety of proportional doses of fentanyl oral soluble film in patients with transitory exacerbation cancer pain.	An open, non-comparative multicenter study	Fentanyl oral soluble film	The dose of fentanyl oral soluble film proportional to the opioid regimen for basal pain treatment is effective and well-tolerated for the treatment of patients with transitory exacerbation cancer pain.
Guitart et al.³⁴	Assess the effect of sublingual fentanyl tablets for pain relief, quality of life and adverse effects in cancer pain patients according to cancer stage and basal opioid regimen	Qualitative study	Sublingual fentanyl tablets	Subgroup exploratory analyses demonstrate the efficacy and safety of sublingual fentanyl tablets for treating transitory exacerbation cancer pain, regardless of cancer stage and basal opioid regimen.
Masel et al.³⁵	Document the feasibility of fentanyl oral tablets for the treatment of patients with transitory exacerbation cancer pain.	Prospective study	Fentanyl oral tablets	Treatment with fentanyl oral tablets led to quick pain relief and reductions in the number of episodes of transitory exacerbation cancer pain. Patient satisfaction was rated as excellent or good.
Peng et al.³⁶	Compare the efficacy and adverse effects of patient-controlled intravenous analgesia with hydromorphone, sufentanil, and oxycodone in the treatment of patients with advanced cancer and pain.	Retrospective serial study	Patient-controlled intravenous hydromorphone, sufentanil, and oxycodone	There was no significant difference in analgesic effect and adverse effect between hydromorphone, sufentanil, and oxycodone.
Yamada et al.³⁷	Assess the effect of continuous pain management interventions and opioid-induced adverse effects on outpatients with cancer	Systematic review	Opioids	Pharmacist interventions can help to adequately achieve the management of pain and adverse effects through interviews and ongoing assessments of cancer patients prior to consultations with physicians, which underlines the importance of pharmacist interventions.

Drugs	Presentation, doses	Therapeutic doses/interval	Effects (start/peak/end)
Fentanyl	Patches 5, 10 and 20 mg	5-20 mg/7 days	24 hours/72 hours
Morphine	Capsules, 10 and 30 mg Oral solution, 10 mg/mL Ampoules, 1 mL-10 mg/mL	5-200 mg/4 hours (oral dose)	15 min/2 hours/4 hours
Morphine LC	Capsules, 30, 60 and 100 mg	30-100 mg/8 to 12 hours	1 hour/6 hours/14 hours
Oxycodone	Capsules, 10, 20 and 40 mg	10-40 mg/12 hours	1 hour/8 hours/25 hours
Hydromorphone	Extended release tablet, 8, 16 and 32 mg	8-32 mg/24 hours	6 to 8 hours/24 hours
Methadone	Capsules, 5 and 10 mg Ampoules, 10 mg/mL	10-50 mg/6 to 12 hours	1 hour/12 hours/25 hours
Buprenorphine	Patches, 5, 10 and 20 µg	5-20 µg/7 days	18 to 24 hours/72 hours/7 days

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Absorption	Distribution
Reduction of: • Splanchnic blood flow • Gastric secretion • Absorption surface • Gastrointestinal motility Increased gastrointestinal pH	Reduction of: • Plasma volume (8%) • Cardiac output • Body water (25%) • Plasma albumin (20%) • Replacement of muscle mass with fat (30 to 40%) Increased gastrointestinal pH
Metabolism	Excretion
Reduction of: • Liver mass • Hepatic blood flow (40%) Change in enzymatic activity (cytochrome P450) Change in phase I of metabolism (hydroxylation, oxidation, hydrolysis, and n-demethylation)	Reduction of: • Kidney mass • Number of functional nephrons • Renal blood flow (1-2% per year, reaching 50% in old age) • Glomerular filtration (30 to 50%) Increased incidence of spontaneous glomerular sclerosis