Transdermal Opioids and the Quality of Life of the Cancer Patient: A Systematic Literature Review

Abstract

Objective:

This systematic literature review aims to evaluate the effectiveness of transdermal opioids in managing cancer pain and their impact on the quality of life (QoL) of patients.

Data sources:

A systematic literature review conducted following the PRISMA protocol, focusing on randomized clinical trials found in the Lilacs, Embase, PubMed, and SciELO databases over the last 20 years.

Study selection and data extraction:

We included randomized clinical trials, published in English, Portuguese, or Spanish, which assessed the impact of transdermal opioids on the QoL. Data extraction was facilitated using the Rayyan app.

Data synthesis:

Six articles meeting the inclusion and exclusion criteria were analyzed. These studies covered a population ranging from 24 to 422 cancer patients experiencing moderate to severe pain. The risk of bias was assessed in each study, generally being categorized as uncertain or high.

Relevance to patient care and clinical practice:

The findings indicate that the analgesic effectiveness and side effects of transdermal formulations (specifically buprenorphine and fentanyl) for managing moderate to severe cancer pain are comparable to, or in some cases superior to, those of oral opioids traditionally employed.

Conclusions:

Transdermal therapy was suggested to have several advantages over oral opioid therapy in enhancing cancer patients’ QoL. These benefits span various dimensions, including pain management, physical functioning, mental health, vitality, overall patient improvement, anger/aversion, strength/activity, general QoL, cognitive and emotional functions, fatigue, and insomnia.

Keywords

opioid analgesics transdermal administration buprenorphine fentanyl quality of life

Introduction

Pain is an unpleasant sensory and emotional phenomenon prevalent among cancer patients, adversely affecting survival and quality of life (QoL).^1,2 Approximately 30% to 50% of cancer patients suffer from moderate to severe pain.² The prevalence rate of pain among 117 combined studies was 39.3% after curative therapy, 55% during cancer therapy, and 66.4% in terminal stages.¹ Thus, a significant number of patients endure persistent pain through various stages of their illness.

Opioids are first-line medications in the treatment of cancer pain, with current guidelines advocating for the administration of potent opioids in minimal dosages for managing moderate pain.^3-6 Oral administration is the preferred route for pain treatment. However, alternative routes are considered when oral administration is impracticable due to bowel obstruction, emesis, dysphagia, and profound confusion.^3,4,7-10

Among the long-acting opioids, buprenorphine and fentanyl are available in transdermal patches and are considered an alternative for cancer patients, especially when administration via the oral delivery is unfeasible.^3,4,11,12 Literature suggests transdermal buprenorphine and fentanyl are efficacious analgesics, exhibiting potencies 75 to 100 times greater than oral morphine, offering an alternative for managing intractable pain.¹¹

The assessment of the human impact of cancer is important in terms of public health and in establishing more effective therapies to improve QoL.¹³ The WHO conceptualizes QoL as “an individual’s perception of their position in life in the context of the culture and value systems in which they live and in relation to their goals, expectations, standards and concerns.”¹⁴ This broad and encompassing concept is characterized by subjectivity, multidimensionality, and bipolarity and includes several aspects that permeate life, including the economic, the social, the cultural, and the political. A particular measure frequently utilized in research to assess QoL is health-related quality of life (HRQoL), linking aspects such as perceived health status, long-term conditions, well-being, life satisfaction, happiness, treatment-related symptoms, and physical, psychological, and social capacities.^15,16 Health-related QoL encompasses a comprehensive evaluation including at least physical, emotional, and social dimensions, while also integrating domains like cognitive function, pain, fatigue, sexuality, and spirituality. Pain experience and psychosocial factors, such as cognitive appraisals and expectations, are significantly associated with an individual’s health status, work productivity, daily activity impairment, health care resource use, and economic burden.¹⁷ Pain-related outcomes, including more intense pain, more disability, and psychological symptoms, may worsen QoL scores.¹⁸ Moreover, long-term conditions like cancer rank among the ailments profoundly impacting individual’s health, with treatments potentially leading to physical limitations and psychological and social harm that must be ascertained and addressed.^19,20

Some instruments are used to assess the QoL of cancer patients, such as the Quality of Life Questionnaire Core 30 (QLQ-C30) of the European Organization for Research and Treatment of Cancer (EORTC), the most frequently utilized, followed by the Functional Assessment of Chronic Therapy-General (FACT-G).^16-23 In addition, generic tools, such as the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36), Word Health Organization Quality of Life (WHOQOL), EuroQol-5D (EQ-5D), and Nottingham Health Profile (NPH), are also used for several long-term diseases.²⁴

The aim of this article is to conduct a systematic literature review on the efficacy of fentanyl and buprenorphine transdermal opioids in alleviating cancer pain and their effect on QoL.

Methods

Study Protocol and Registration

This investigation is a systematic literature review executed following the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses)²⁵ framework and was preregistered on PROSPERO (registration number CRD42021244447).

Inclusion Criteria

The PICOS strategy encompassses: Population—cancer patients without restrictions on age, race, or gender; Intervention—transdermal opioids (buprenorphine and fentanyl); Comparison—with other oral opioids for managing moderate to severe pain or placebo; Outcomes—Enhancement of QoL and pain mitigation; Study (Type of study)—Randomized Clinical Trial (RCT) in English, Portuguese, or Spanish.

Exclusion Criteria

Scientific articles about opioids with nontransdermal formulation, studies published outside the specified timeframe, research on nononcologic pain management, non-RCTs, studies lacking relevant outcomes, reports with incomplete or inaccurate data, and duplicate publications were excluded (retaining the most comprehensive).

Search Strategy

Scientific papers indexed in the Lilacs, PubMed, EMBASE, and SciELO databases, published between January 1999 and December 2023, were included in the study. The research was conducted by combining the descriptors of transdermal opioids, cancer pain, and QoL. The comprehensive search strategy for each database is available in the Supplementary Material.

Study Selection and Data Extraction

Two reviewers (PSK and ESRB) independently conducted the literature search. The titles and abstracts of retrieved articles were browsed to exclude irrelevant studies, and then the full texts of the remaining articles were read to identify eligible studies. The authors performed data extraction after reading the full text of the selected articles. The extracted data included the authors’ names, year of publication, country of study, number of participants in the study, age and sex, type of cancer, intervention performed, outcomes, instrument applied to measure QoL, and statistical significance. Subsequently, a third reviewer (DCK) confirmed the data accuracy. The data from the articles were extracted with the assistance of the Rayyan app.²⁶

Quality Assessment of Included Studies

The risk of bias was assessed using the COCHRANE Risk of Bias tool for randomized trials (RoB 2),²⁷ which was independently assessed by 2 reviewers (PSK and ESRB), and any areas of disagreement were discussed with a third reviewer (DCK).

This tool²⁷ covers 5 specific domains for assessing the risk of bias: randomization; deviations from the intervention; lack of data; measurement of the outcome; and selection of the outcome. Ultimately, an overall risk of bias for each article was determined, with judgment in each domain categorized as “low risk,” “high risk,” or “some concerns” to denote an uncertain risk level.

Results

The database search, following the application of filters based on pre-established inclusion and exclusion criteria, resulted in 564 articles. After removal of duplicates, 519 articles remained. Upon review of the titles and abstracts of these articles, 492 were excluded, leaving 27 for full-text review. After evaluation, 6 articles^28-33 were included in the review. The flowchart illustrating the study selection process, along with the reasons for exclusion, is presented in Figure 1. Details of the included studies can be found in Tables 1 to 3.

Table 1.

Characteristics of the Selected Studies.

Author	Country	Study duration	Study population	Type of cancer	Pain intensity
Leppert and Nosek³³	Poland	28 d	53	14 patients with lung cancer, others not specified.	Severe/intense
Nosek et al³⁰	Poland	28 d	53	GI cancer, lung, colon, breast, prostate, urinary system, uterus, stomach, esophagus.	Severe/intense
Mercadante et al³²	Italy	3 years	70	Breast (16) + others not specified.	Moderate to intense
Pace³¹	Italy	8 weeks	52	Abdominal neoplasia	Moderate to intense
Mystakidou et al²⁹	Greece	7 years	422	Bone metastasis	Moderate to intense
Pistevou-Gompaki et al²⁸	Greece	7 years	24	Bone metastasis	Moderate to intense

Table 2.

Demographic Data Found in the Studies.

Author	Study population	Age	Gender	Education	Family status	Type of cancer
Leppert and Nosek³³	53	Without information	Without information	Without information	Without information	Without information
Nosek et al³⁰	53	Average of 62 years	Female: 25 Male: 28	Without information	Without information	Gastrointestinal system and lung cancer
Mercadante et al³²	70	18–78	Female: 34 Male: 36	Without information	Without information	Breast cancer and nociceptive-neuropathic syndromes
Pace³¹	52	Average of 54 years	Female: 25 Male: 27	Without information	Without information	Abdominal neoplasia and cancer long-term pain
Mystakidou et al²⁹	422	25–88	Female: 203 Male: 219	40.28% have education secondary	70.38% are married	Kidney/bladder, lumbar spine, brain
Pistevou-Gompaki et al²⁸	24	54–82	Female: 7 Male: 17	Without information	Without Information	Lung, thoracic and lumbar spine, lymph, and liver

Table 3.

Comparative Analysis of the Results of the Selected Articles.

Author	Intervention/patients	Objective of the study	Analgesia (P < .05)	Adverse effects	Quality of life	Results (P < .05)
Leppert and Nosek³³	BT/17 FT/15 MO/14 OX/16	Compare patients quality of life with cancer pain treated with oral morphine CR, oral oxycodone CR. transdermal fentanyl or buprenor-phine	Similar analgesic efficacy: EORTC-QLQ-C15-PAL	Nausea, loss of appetite worsened with the duration of treatment in all groups (P < .05): EORTC-QLQ-C15-PAL	Better physical functioning with MO (P < .05): EORTC-QLQ-C15-PAL	Improvement: ESAS: sleepiness, nausea, appetite, fatigue, anxiety, depression, pain. HADS: severity and intensity of anxiety, depression. EORTC-QLQ-C15-PAL Improvement: emotional function, pain, fatigue, insomnia, overall QoL. Worsening: EORTC-QLQ-C15-PAL: nausea and loss of appetite. Difference among the groups: EORTC-QLQ-C15-PAL: physical functioning (morphine had more favorable results)
Nosek et al³⁰	MO (20–80 mg/d)/14 OX (10–60 mg/d)/16 BT (35–140 µg/h)/17 FT (25–100 µg/h)/15	Compare the analgesic effect and adverse effects of oral morphine and oral oxycodone with transdermal buprenor-phine and fentanyl in cancer patients with intense pain.	Similar analgesic efficacy: BPI-SF	Sleepiness, nausea, and appetite worsened in all groups (P < .05). ESAS	Pain improvement in the capacity to walk and normal work in the group treated with MO (P < .05): BPI-SF	Improvement (regardless of the predominant mechanism): BPI-SF: general pain, the effect of pain on general activity, interpersonal relationships, pleasure in life, sleep, mood, and capacity to walk and regular work. ESAS: anxiety, fatigue, and wellness. Worsening: ESAS: severity of sleepiness, nausea, appetite. Difference among the groups: BPI-SF: Beneficial effect on the improvement of pain in the capacity to walk and normal work (morphine).
Mercadante et al³²	ME (15 mg/d)/23 FT (25 µg/h)/25 MO (60 mg/d)/22	Compare the effect of methadone, transdermal fentanyl, and morphine, their efficacy, adverse effects, need to increase opioids and quality of life in patients with advanced cancer undergoing treatment with these medications.	Similar analgesic efficacy: Numeric pain rating scale 1-10 Dose increase was less necessary in the ME group.	Adverse effects not detailed. However, the use of medication to control adverse effects showed no significant differences among the groups (P = .84).	Spitzer QoL: No significant differences among the groups. Statistical significance not specified/informed.	The variation in dose increase was lower in the group treated with methadone.
Pace³¹	BT (35 µg/h)/26 MO (60 mg/d)/26	Assess the analgesic effect of transdermal buprenor-phine to control long-term cancer pain versus sustained-release morphine, combined, in all cases, with oral tramadol (if necessary).	Superior efficacy of buprenor-phine	More prevalent with MO, but with no statistical significance: vertigo, headache, sleepiness, constipation, confusion, and nausea.	Improvement in physical pain, mental health, and vitality in the group treated with BT (P < .05): SF-36 Patient’s global improvement impression with BT (P < .05): PGIC Improvement in anger/aversion, strength/activity, and mood with BT (P < .05): POMS Less extra analgesia with BT.	Pain mean score of 2 to 8 and mean score of sleep interference with improvement in the group treated with buprenorphine. PGIC: more expressive improvement in the group treated with buprenorphine. POMS: Improvement in the group treated with buprenorphine: anger/aversion, strength/activity fatigue/inertia, total mood disorder. SF-36: Improvement in the group treated with buprenorphine: physical pain, mental health, and vitality. Additional analgesia: less extra analgesia in the group treated with buprenorphine.
Mystakidou et al²⁹	FT(25 uh/h)/201 C/P(120 mg/d)/221	Assess the efficacy of transdermal fentanyl (25 µg) compared with codeine/paracetamol (500 mg) associated with radiotherapy for bone metastatic cancer pain and the outcomes in pain management and quality of life of these patients.	More favorable with FT: BPI	Higher in the C/P group: constipation, sleep disorder, nausea. Statistical significance not reported/demonstrated.	Improvement in QoL in all groups with the more favorable trend with FT: ECOG. However, the statistical significance was not demonstrated/reported. Patients’ overall satisfaction was more favorable with FT (P < .05).	GBPI and overall satisfaction: more favorable results in the group treated with transdermal fentanyl.
Pistevou-Gompaki et al²⁸	FT(25 µg/h)/11 C/P(500 mg/d+30 mg/d)/13	Compare the analgesic effect of the transdermal fentanyl (25 µg) or paracetamol and codeine (500 mg/day) (P/C) associated with radiotherapy in patients with painful bone metastasis.	Analgesic efficacy in both; VAS, G-BPI Greater pain relief with FT: VAS	Not specified.	Significant improve-ment in overall quality of life, physical, cognitive, and emotional functions; fatigue, insomnia, and QoL in the FT group. G-BPI	VAS: Pain improvement in both groups. Greater pain relief with TTS-fentanyl compared with C/P. G-BPI: Pain improvement in both groups. Significant improvement in overall quality of life, physical, cognitive, and emotional functions, fatigue, insomnia, and overall QoL in the TTS-fentanyl group.

Characteristics of the Studies

The included studies were published between 2004 and 2019, most were before 2010 (71.42%), all in English. The size of the samples varied from 24 to 422 participants, with pain intensity ranging from moderate to severe. Studies lasted between 8 and 49 days and were performed in 3 countries: Italy, Poland, and Greece. Information about participants’ age and sex were available in most of the included studies, with the type of cancer varying accordingly.

Analysis of Included Studies

The Leppert and Nosek³³ study compared groups of patients treated with oral controlled-release (CL) morphine, oral CL oxycodone, transdermal fentanyl, and transdermal buprenorphine, in 53 patients with a 28-day follow-up. Immediate-release (IR) morphine was administered orally in all patient groups as a rescue opioid for breakthrough pain. Patients were required to have intact cognition as per the Mini-Mental State Examination (MMSE) scores within the normal range. A total of 17, 16, 15, and 14 patients were treated with buprenorphine, oxycodone, fentanyl, and morphine, respectively. The authors observed that all medications provided adequate analgesia, reducing the pain, with no significant differences among the groups. In the analysis of QoL by the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 15 PAL (EORTC QLQ-C15-PAL), the duration of treatment had a positive effect on emotional function, pain, fatigue, and overall QoL. The subjects treated with morphine experienced a greater effect on physical functioning than the other groups (P < .025), and morphine also tended to be more beneficial than other opioids regarding depression (P = .051). However, no other domain presented a significant difference among the studied groups. In the Bowel Function Index (BFI) analysis, there were no significant differences in the severity of constipation among opioids. This study did not specify the doses of the medications used.

Nosek et al³⁰ compared oral CL morphine (N = 14), oral CL oxycodone (N = 16), transdermal fentanyl (N = 15), and transdermal buprenorphine (N = 17), stratifying patients based on the predominant pain mechanism into nociceptive pain (N = 32) and neuropathic pain (N = 30). Opioid dosages were adjusted to optimize analgesia (numerical rating scale [NRS] of 4) while minimizing adverse effects. For all patient cohorts, the rescue opioid used for the treatment of breakthrough pain episodes was IR morphine administered via the oral route, titrated to achieve a satisfactory analgesic effect. The dosage ranges for the studied opioids were 35 to 140 µg/h for buprenorphine, 25 to 100 µg/h for fentanyl, 10 to 60 mg/day for oxycodone, and 20 to 80 mg/day for morphine. This investigation underscored that the duration of treatment significant influenced the analgesic outcome more than the type of therapy employed, irrespective of the underlying pain mechanism (neuropathic or nociceptive). Within all parameters of the Brief Pain Inventory-Short Form (BPI-SF) (pain at its worst, pain at its least, pain on the average, pain right now), a marked reduction in pain intensity was observed throughout the treatment period, with no discernible differences across the 4 opioid regimens. A highly significant time effect and interactions of treatment time and type of opioid therapy were noted in all items of pain intensity. In the BPI-SF, the effect of pain on general activities, work, interpersonal relations, pleasure in life, sleeping, and mood was also significant as a function of treatment duration, especially in the first 14 days (P < .001), with no significant difference among the groups. In the group treated with morphine, the reduction of pain intensity led to improved walking capacity (P < .021) and had a significant difference as a function of treatment duration (P < .001). Furthermore, the alleviation of pain intensity notably improved normal work performance in the morphine group (P < .017), albeit this effect was more influenced by treatment duration than the choice of medication (P < .001). Over the 28-day treatment period, average dosage adjustments for the opioids were calculated at 80% for buprenorphine, 216% for oxycodone, 80% for fentanyl, and 183% for morphine. The administration of IR morphine for breakthrough pain across all patients, expressed in milligrams (mean ± standard deviation), was documented at 457.65 ± 479.47 for buprenorphine, 338.13 ± 273.94 for oxycodone, 90.67 ± 377.48 for fentanyl, and 260.00 ± 327.04 for morphine. According to the authors, the group of patients with neuropathic pain required more rescue and adjuvant medications (dexamethasone, antiepileptic, antidepressants, and paracetamol) compared to the group with nociceptive pain, but no statistical analysis was reported. Adverse effects were evaluated using the ESAS (Edmonton Symptom Assessment System) and BPI tools. According to the ESAS, the intensities of drowsiness, exacerbation of nausea and diminished appetite varied with treatment duration (P = .009), mainly in the first 9 days, followed by a subsequent decline. There was also a reduction in anxiety, fatigue, and improvement in wellness associated with the treatment duration (P < .001) in all groups. No significant differences were found in the BFI concerning the proposed treatments or treatment duration, which was attributed to constipation prophylaxis. In the analysis of QoL by the EORTC-QLQ-C15-PAL, the authors mentioned improved physical function domain in the group treated with morphine. An overall improvement in QoL was reported, yet specific data were not disclosed.

Mercadante et al³² conducted a 4-week comparative study on the analgesic efficacy and QoL among 108 advanced cancer patients treated with CL oral morphine (MO, 60 mg/day), oral methadone (ME, 15 mg/day), or transdermal fentanyl (FE, 0.6 mg/day). Totals of 22, 25, and 23 patients in groups MO, FE, and ME groups, respectively, completed the study period. No significant differences were noted regarding age, sex, the period required to stabilize the medication, pain mechanism, or the relationship between opioid dosage and pain intensity. The initial dose of the opioids used varied during the study. Most were increased during the treatment, except for the group treated with methadone (OEI—opioid escalation index as a percentage % [Mean _95% confidence interval (CI)] was 0.64 [0.06-1.34]), in which the range between the initial and final doses was lower than that of the other medications (P < .001). Most of the patients taking methadone kept the initial dose of 15 mg/day or less after 4 weeks of use. At the end of the study, the average dose used for MO, FE, and ME were 82.7, 1.18, and 7.7 mg/day, respectively. Pain intensity was reduced in the 3 groups (P < .05). Patients started with a mean pain intensity of 7.0 (ME, MO, FE), and at the end of the study, the mean was 3.4 for ME, 2.5 for MO, and 2.4 for FE. Concerning the QoL score used in the study, the Spitzer Quality of Life (Spitzer QoL), which assesses daily life, activity, health perceptions, social support, and behavior showed no significant differences among the studied groups. The authors presented the Spitzer QoL mean scores obtained over the 4 weeks of the study for the 3 groups (methadone, morphine, and fentanyl). The methadone group began with a score of 5.6 and ended with 5.2; the morphine group, 5.8 and 5.4; the fentanyl group, 6.0 and 6.1.

Pace³¹ compared transdermal buprenorphine (BT, 36 µg/h) and CL morphine (MO, 60 mg/day) in 2 patients cohorts evaluated after 2, 4, and 8 weeks of treatment. Candidates were chosen based on a history of cancer-related long-term pain spanning 1 to 3 years, and a pain score of at least 40 mm on the Visual Analog Scale (VAS) of the Short-Form McGill Pain Questionnaire (SF-MPQ). The investigators found significant differences between the BT and MT groups at the endpoint regarding the average pain score, the average score for interference with sleep, and the total scores on the VAS, PPI (Present Pain Intensity), and SF-MPQ (Short-Form McGill Pain Questionnaire). According to the SF-MPQ, patients who received transdermal buprenorphine showed a significantly lower average total pain score (total score) (P < .01), average VAS score (P < .01), and average PPI score (P < .01) at the second, fourth, and eighth weeks compared to patients treated with morphine sulfate. Concerning the global impression improvement scale (PGIC), these patients had better results than the group treated with morphine. Approximately 65.4% of patients in the BT cohort achieved at least “moderate” improvement by the treatment’s end on the PGIC scale, whereas only 33% of patients of the MO group exhibited a similar level of enhancement. In the Profile of Mood States (POMS), patients treated with buprenorphine had a more significant improvement than those on morphine in the items of anger/aversion (P < .001), strength/activity (P < .001), fatigue/inertia (P < .05), and total mood disorder (P < .05). Conversely, patients receiving morphine displayed enhancements in QoL scores within the domains evaluated by the SF-36 QoL: physical pain (P < .01), mental health (P < .03), and vitality (P < .001). In all the other items of these questionnaires, buprenorphine showed positive results, but there were no significant differences compared to morphine. In addition, the need for additional analgesia (measured by a visual analog scale [VAS] of 40) was compared to analyze the efficacy on patients followed in both groups. All groups required more analgesia (tramadol) after the first week of treatment. Among the 42% of patients in the buprenorphine group, 7 received 100 mg/day and 4 received 200 mg/day of tramadol. Of the 61% of patients in the group treated with morphine, 7 received 100 mg/day and 9 received 200 mg/day of tramadol. This proportion decreased to 11% in the group treated with buprenorphine and 42% in the group treated with morphine in the second week, when dosages were adjusted to 52.5 µg/h of transdermal buprenorphine and 90 mg/day of morphine sulfate, respectively. Adverse events such as vertigo, headache, sleepiness, constipation, confusion, and nausea were more prevalent in the morphine group, as was the utilization of symptomatic medications (metoclopramide for emesis or laxatives for constipation), yet no statistical difference were evident among the groups. This study prohibited the use of antiepileptic drugs, antidepressants, anti-inflammatories, muscle relaxants, and other opioids.

Mystakidou et al²⁹ performed a comparative analysis of cancer patients with bone metastasis and moderate to intense pain treated with radiotherapy plus codeine/paracetamol (C/P) or radiotherapy plus transdermal fentanyl, divided into 2 groups with 221 and 201 patients, respectively. Assessements were made before and after the treatment (72 hours; 7, 14, and 28 days; and 2 months). Standard information gathered on the patient’s diary card at every visit encompassed QoL, Greek-Brief Pain Inventory (G-BPI), overall treatment satisfaction, European Collaborative Oncology Group (ECOG) status, side effects, and use of concomitant medications. The initial dose of transdermal fentanyl was 25 µg/h per 72 hours and that of codeine/paracetamol was 120 mg/day. Patients receiving codeine/paracetamol required dose increases to 240 mg/day (20% of patients) and 360 mg/day (86.5%). Of those treated with transdermal fentanyl, 6% escalated the fentanyl dosage to 50 vg/h. Patients in the transdermal fentanyl group were also allowed to use codeine/paracetamol in the initial 12 hours following the application of the fentanyl patch, though the dosage and number of patients availing this were not reported. Summary statistics revealed progressive enhancements in QoL, ECOG score, pain management, G-BPI (questions 5, 9i, and 9ii), and overall treatment satisfaction for the 2 groups. Significant results were observed in all parameters of the G-BPI, with a greater reduction in pain in the group treated with transdermal fentanyl (P < .05), as well as better satisfaction with the treatment in this group (P < .05), assessed by the self-rating scale of 4 points. The most common side effects were constipation, sleep disorders, and nausea (higher incidence in the group treated with C/P), but with no statistical significance, compared with the other studied groups. The Performance Status Scale (ECOG) indicated a more favorable trend in transdermal fentanyl group, although improvements were noted across all groups post-treatment initiation.

Pistevou-Gompaki et al²⁸ compared the analgesic effect of the transdermal fentanyl (TTS-fentanyl) 25 µg/h or paracetamol and codeine (P/C) 500 mg/day associated with radiotherapy in patients with painful bone metastasis: (lung [8]; prostate [7]; breast [4]; unknown [1]; stomach/gallbladder [3]; kidney [1]; multiple myeloma [2]). Pain was assessed using a 10 cm Visual Analogue Scale (VAS). Quality of life was measured using the G-BPI. Evaluations were performed prior to radiotherapy, biweekly during treatment sessions, and 3 months posttreatment. In both groups, there was a significant improvement in all measured scores at 3 months post baseline (P < .01, Wilcoxon test). However, at the end of the study, the mean score in the TTS-fentanyl group represented almost complete pain relief (1.1 out of a maximum of 10) compared to a moderate level of pain in the P/C group (4.3/10). Visual analog scale values (P < .01, Kruskal–Wallis test). The mean pain scores fell gradually during radiotherapy, reaching a maximum reduction 7 weeks postirradiation in both groups. As with the pain score, the degree of QoL improvement was significantly greater with TTS-fentanyl than in the P/C group (P < .05 in all cases). Transdermal-fentanyl was linked to enhancements in functional domains (physical, role, cognitive, emotional, social), insomnia, fatigue, pain (worst, least, average, current) (P < .001). Consequently, ate the study’s conclusion, the TTS-fentanyl group reported a near-normal QoL (96%) compared with considerable impairment in the P/C group (51%).

The opioid-related side effects comprised mild nausea and vomiting in 4 (29%) patients receiving TTS-fentanyl and severe vomiting in 3 (25%) patients receiving P/C, which was effectively managed with antiemetics.

Tables 1 and 2 outline the demographic data and intervention characteristics of the selected studies, along with observations on analgesic efficacy and QoL. Table 3 presents a comparative analysis of the outcomes from the evaluated studies.

Risk of Bias in Included Studies

The risk of bias in the included studies is summarized in Figures 2 and 3.

Randomization process

The randomization process was deemed appropriate in 3 studies.^30-32 However, 3 studies did not detail their randomization process and were consequently categorized with some concerns.^28,29,33

Intervention

A low risk of bias related to intervention deviations was identified in all included studies.^28-33

Outcome

All studies^28-33 were deemed adequate regarding the reporting of missing data, a component of RoB 2’s third item. Yet, in the fourth item, one study was identified as having a high risk of bias²⁸ due to insufficient information on blinding and the study protocol. The remaining 5 studies^29-33 were classified as some concerns, given their open-label randomized clinical trial nature.

Selective reports

Two articles^30,33 were classified as having a low risk of selective reporting. The other 4 articles^28,29,31,32 were categorized with some concerns due to the absence of details regarding the clinical trial protocol.

Discussion

Pain relief remains the primary objective for prescribers addressing this symptom.³⁴ Pain management has been linked to improvements in QoL (physical functioning, emotional well-being, overall QoL) in cancer patients as determined through specific assessment tools.³⁵ The studies reviewed in this article suggest that transdermal fentanyl and buprenorphine exhibit similar or superior analgesic efficacy compared to other opioids. The analgesic equivaalence of the transdermal formulation was perceived in comparisons with morphine, oxycodone, and methadone, while the analgesic superiority of transdermal buprenorphine or fentanyl was established relative to morphine and codeine/paracetamol, respectively. Furthermore, the review findings indicate a comparability in QoL outcomes between transdermal buprenorphine and fentanyl versus morphine. However, transdermal formulations are associated with a reduced incidence of adverse effects.

Transdermal buprenorphine and fentanyl have been recognized for effective pain relief, higher bioavailability, and reduced plasma concentration variability compared oral opioid formulations, as they circumvent the first-pass hepatic metabolism.^36-38 These data corroborate this review, where the selected studies showed an analgesic efficacy of the transdermal formulation equal to or greater than that of oral opioids commonly used to treat cancer pain. Moreover, the literature records suggest that transdermal buprenorphine has a lower association with adverse effects such as tolerance and respiratory depression induction.³⁹ In this article, transdermal buprenorphine, compared with oral morphine, was associated with less vertigo, headache, sleepiness, constipation, confusion, and nausea. Although half of the studies included in this review indicated that the presence of adverse effects commonly associated with opioid use (sleep disturbances, nausea, and constipation) were less frequent with the transdermal formulations, data on statistical significance were not provided.

The analgesic effectiveness of transdermal fentanyl in managing cancer pain has also been well-documented.² A Cochrane review involving 1,244 participants observed significant pain reduction in cancer patients treated with transdermal fentanyl compared with oral opioids and with less constipation, nausea, and vomiting when compared with oral morphine.⁴⁰ Conversely, skin rash and pruritus were deemed infrequent, albeit concerning, side effects of transdermal applications. While these findings allign with the outcomes of this study, where transdermal fentanyl was linked to improved analgesic effect and lower incidence of constipation, sleep disturbances, and nausea, the statistical significance of these observations was not reported. Moreover, this review draws a comparison between a potent opioid (fentanyl) and a weaker opioid (codeine), presenting a challenge for accurate analysis due to the disparate analgesic potencies.² However, another investigation contrasting transdermal fentanyl with oral morphine showed similar analgesic efficacy but with less induction of adverse effects, especially constipation, having a more satisfactory evaluation by patients, and fewer cases of treatment discontinuation.⁴¹ Therefore, transdermal formulations [fentanyl and buprenorphine] are associated with an equal or superior analgesic effect in relation to oral opioids and less-adverse effects such as constipation, nausea, sedation, sleepiness, and urinary retention, which are positive factors for these patients’ QoL. These medications do not accumulate active metabolites and may offer a viable therapeutic option for patients with renal impairment, as they do not necessitate dosage adjustments.⁴²

Pain exhibits a negative correlation with QoL in cancer patients.³⁵ In general, the symptoms have a significant impact on patients. The more intense the burden of symptoms, the higher the level of emotional sorrow, commitment with physical and social performance, and overall QoL.⁴³ A review with 768 cancer patients showed that the impact on the QoL of these patients is multifactorial and has repercussions in several domains: 85.5% (inferior physical performance), 92.7% (lack of support), 72.9% (affected physical well-being), 71.7% (sleep disruption), and 97.1% (urinary issues). Furthermore, sexual function, cognition, and wellness were compromised in the process of the disease. This review showed that patients treated with transdermal formulations had more positive effects of the treatment on QoL in several domains, with significant differences in relation to oral opioids such as morphine and codeine/paracetamol. Patients treated with transdermal buprenorphine (35 µg/h) showed an improvement in physical pain, mental health, and vitality by SF-36 (P < .05); global impression of improvement by PGIC (P < .05); and anger/aversion, strength/activity, and mood by POMS (P < .05), compared with oral morphine. Patients treated with transdermal fentanyl (25 µg/h) had significant improvement in the overall QoL, physical function, cognition, emotional, fatigue, insomnia, and overall QoL by G-BPI (P < .05) and better overall satisfaction with the treatment (P < .05), in relation to those treated with codeine/paracetamol (500 mg/30 mg/d). These data coincide with some literature studies that show a significant improvement in QoL in patients treated with transdermal buprenorphine⁴⁴ and transdermal fentanyl.^42,45 Despite these outcomes, employing acetaminophen with codeine as a comparator may introduce biases. Oncology patients typically require stronger opioids for pain management, and acetaminophen with codeine might not provide equivalent efficacy. This disparity in control analgesic potency could influence group comparisons and affect the validity of these study results. Therefore, it is imperative to acknowledge this limitation in interpreting trial findings and to approach their conclusions with caution.

The evaluation of cancer patients’ QoL before and after treatment is essential and encompasses various dimensions, including the physical, psychological, social, and spiritual aspects.⁴⁶ A recent study in Asian cancer patients experiencing pain revealed that patients who received TD buprenorphine reported improvements in overall QoL. Among the 5 functional scales of the EORTC QLQ C-30, only social functioning significantly improved over time; there was no significant change over time for physical, role, emotional, or cognitive functioning. Regarding cancer-related symptoms, TD buprenorphine also lessened the severity of nausea/vomiting, insomnia, and constipation.⁴⁷

Patient treatment should be personalized, taking into account the multifaceted impact on their QoL and addressing the persistently issue of inadequate analgesia in the context of subtherapeutic dosing in numerous instances, which constitutes a significant public health concern.

Limitations of the Study

Differences in population size, the absence of detailed information regarding the age and sex of the participants, variability in the type and stage of cancer, chemotherapy regimen received, type of pain, treatment duration, recurrence rates, disease duration, instruments used, other comorbidities contributing to pain, and the use of coadjutant and rescue medications constituted the limiting factors of the selected studies. Consequently, it was challenging to perform a meta-analysis due to the limited number of included studies, their heterogeneity, and the presence of missing data.

The comparison of variables assessed through various instruments represents a significant limitation in analyzing the efficacy and impact of medication on QoL. In certain studies,^32,34 the included patients had already been treated with opioids. This was an exclusion criterion in other studies, complicating comparisons as sensitization may influence the analgesic response to these medications. Furthermore, the distinction between weak and strong opioids and the use of rescue with weak opioids were not considered in the results analysis. These factors contribute to the methodological limitations previously identified in the literature. In Cochrane’s analysis, a compilation of systematic reviews including 152 studies about the efficacy and adverse effects of opioids used in cancer pain, few studies featured a control group or placebo, in addition to exhibiting variable populational sizes, diverse or inclonclusive results, and a maximum in GRADE assessment of quality, yielding very low evidence according to Cochrane.² Another limitation arises from the selection of acetaminophen with codeine as the comparator in 2 trials. This choice may not accurately represent the potency and mechanism of action of transdermal opioids like fentanyl and buprenorphine, potentially skewing the comparison and impeding a comprehensive assessment of their efficacy. Moreover, acetaminophen with codeine might not reflect the standard of care or optimal treatment for the conditions studied, further limiting the generalizability and relevance of our findings. In addition, there is a scarcity of randomized clinical trials on cancer pain control and QoL of cancer patients with appropriate instruments for quality-of-life assessment. Despite the limitations, the connection between QoL and the treatment of long-term cancer-related pain remains a vital topic for discussion. This systematic review is seen as an opportunity to promote more structured randomized studies with enhanced bias control.

Conclusion

This study demonstrates that the analgesic efficacy and the adverse effects of transdermal formulations (buprenorphine and fentanyl) in managing moderate to severe cancer pain are comparable or superior in some instances to those of commonly used oral opioids. The influence of transdermal therapy on various aspects of the QoL of cancer patients is perceived as more benefical than that of other oral opioids, notably in enhancing pain, physical functioning, mental health, vitality, patient’s overall sense of improvement, anger/aversion, strength/activity, general QoL, cognitive and emotional functions, fatigue, and insomnia.

Supplemental Material

sj-docx-1-aop-10.1177_10600280241247363 – Supplemental material for Transdermal Opioids and the Quality of Life of the Cancer Patient: A Systematic Literature Review

Supplemental material, sj-docx-1-aop-10.1177_10600280241247363 for Transdermal Opioids and the Quality of Life of the Cancer Patient: A Systematic Literature Review by Patricia Santos Reis, Durval Campos Kraychete, Emilie de Magalhães Pedreira, Eduardo Silva Reis Barreto, César Romero Antunes Júnior, Vinicius Borges Alencar, Anna Karla do Nascimento Souza, Liliane Elze Falcão Lins-Kusterer and Liana Maria Torres de Araujo Azi in Annals of Pharmacotherapy

Footnotes

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

ORCID iD

Eduardo Silva Reis Barreto

Supplemental Material

Supplemental material for this article is available online.

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