Does the Use of Two Major Opioids Have an Impact on Improving Pain Treatment and Quality of Life in Cancer Patients?—A Literature Review

Shirley Duarte; Marília Dourado; Hugo Ribeiro

doi:10.20944/preprints202411.1102.v1

Submitted:

13 November 2024

Posted:

14 November 2024

You are already at the latest version

Abstract

Cancer pain is a highly prevalent problem and one of the most distressing symptoms in cancer patients. The management of cancer pain is one of the most significant challenges in the care of these patients. Cancer pain must be treated quickly and effectively, as it affects the quality of life and reduces the patient's life expectancy. Major opioids are recognized by the World Health Organization (WHO) as first-line treatment for moderate to severe cancer pain, but their use is often hampered by individual variations, comorbidities, and complications associated with cancer. Since the simultaneous use of two major opioids has become frequent, a narrative review was conducted, whose main objectives were: to evaluate whether the combination of two major opioids improves pain and quality of life in cancer patients, considering their pharmacodynamic and pharmacokinetic properties and evaluate the impact of this combination on the frequency and intensity of side effects. The search for information was carried out in evidence-based medicine databases, namely PubMed/MEDLINE, Cochrane Library, Database of Abstracts of Reviews of Effects, National Guideline Clearinghouse, NHS Evidence and Index das Revistas Médicas Portuguesas using the MeSH terms “opioids” and “quality of life”. Articles and documents published between January 1, 2010 and June 1, 2023, in English, Portuguese and Spanish, were considered, including original articles, meta-analyses, systematic reviews and clinical guidelines. A total of 342 articles were retrieved and of these, only 13 were selected for reading. From the analysis carried out, it was observed that the combination of opioids is based on the principle that different opioids act through different mechanisms, which can reduce dose-related adverse effects. Simultaneous use of two major opioids may allow for more modest increases in the equivalent dose of the second opioid, providing better pain control and reduced side effects such as nausea, vomiting, and constipation. More studies on the combination of larger opioids are needed to improve cancer pain treatment. The lack of personalized therapies limits the effectiveness of opioids, and variability in treatment responses requires individualized approaches. Personalized medicine, based on pharmacogenomics, is one of the most promising strategies to optimize pain relief and reduce adverse effects.

Keywords:

cancer pain

;

opioids

;

pharmacology

;

quality of life

;

pain management

;

adverse effects

Subject:

Medicine and Pharmacology - Anesthesiology and Pain Medicine

Introduction

Pain is defined by the International Association for the Study of Pain (IASP) as “an unpleasant sensory and emotional experience associated, or similar to that associated, with actual or potential tissue damage” [1].

The prevalence of cancer pain may be associated with the stage of the disease and the location of the cancer [2]. Currently, the worldwide prevalence of pain in cancer patients is approximately 50% at diagnosis and approximately 80% in stage III-IV cancer patients, being one of the most feared symptoms associated with oncological disease [2,3].

The frequency and intensity of cancer pain tends to increase as the disease progresses, especially in advanced cases. This type of pain can have multiple etiologies: it can be caused directly by the tumor, such as bone invasion or nerve compression, or it can be a consequence of treatments, including fibrosis induced by radiotherapy, neuropathy caused by chemotherapy and postoperative pain [4,5].

Uncontrolled pain can lead to significant suffering, negatively impacting quality of life, treatment adherence and, ultimately, patient survival. Therefore, pain management in cancer patients requires a multimodal and multidisciplinary approach that considers all possible causes and effects of pain, as well as the overall impact on the patient's life [6,7].

Opioids are essential medications to mitigate suffering and improve quality of life through pain control in patients with oncological pathology [6]. They work by binding to specific receptors in the central and peripheral nervous system, modulating pain perception and providing pain relief. Among the major opioids most used in clinical practice are morphine, tapentadol, oxycodone and fentanyl, drugs with distinct pharmacokinetic and dynamic characteristics that influence their efficacy and adverse effect profile [8].

There are important differences in the pharmacokinetics of major opioids, related to distribution, metabolism and renal elimination. Thus, according to Ribeiro et al. (2021) regarding absorption, all major opioids are absorbed through the small intestine, although fentanyl and buprenorphine can also be absorbed through the skin. Regarding drug distribution, it is important to note that only morphine and hydromorphone are water-soluble, while all other opioids are lipid-soluble. Being all considered as weak bases, they bind with some affinity (10-45%) to acidic plasma proteins, such as alpha1-acid glycoprotein, which generally increases with aging [9].

Regarding metabolization, morphine and Tapentadol are metabolized in phase 2 of hepatic biotransformation, hydromorphone is approximately 70 to 80% metabolized in this phase, while the others are highly metabolized by CYP450 in phase 1 of biotransformation [9,10].

Regarding elimination, both oxycodone and Tapentadol are eliminated mainly via the kidneys. It should be emphasized that buprenorphine has residual elimination via the urinary route, and Fentanyl has large renal elimination (around 75%) but through inactive metabolites [9]. In this sense, they will be those that present fewer pharmacokinetic changes resulting from the loss of renal functionality [11].

The choice of the most appropriate opioids (base and/or rescue) and their dosage are adjusted according to the intensity of pain, the patient's response to treatment and the presence of comorbidities and/or complications of cancer, conditions that make prescription difficult [12,13].

Scientific literature highlights the importance of proper opioid handling to maximize pain relief and minimize side effects. Studies show that, although effective, opioids are associated with several adverse events, including constipation, nausea, vomiting, xerostomia, esophageal reflux, or abdominal discomfort. Therefore, its use must be carefully monitored and adjusted to balance pain relief and quality of life [14,15,16].

Although major opioids are combined in the clinical setting, the use of combinations of major opioids is not considered by the World Health Organization (WHO) analgesic ladder for cancer pain relief [12,17].

Some authors consider that combining two different opioids to treat pain has no advantages, as it may be duplicating therapy with the same mechanisms of action [18,19,20]. However, it is recognized that some opioids have mechanisms of action distinct from those related to mu, delta or kappa receptors. For example, tapentadol has a noradrenergic mechanism and tramadol has a noradrenergic and serotonergic mechanism of action [21,22].

The use of opioid combination therapy may be justified for several reasons. This approach can improve pain control, limit the development of opioid tolerance, and reduce associated side effects. By combining opioids that act on different receptors, it is possible to achieve more effective pain relief while minimizing the impact on mu receptors, thus reducing adverse effects such as nausea, constipation and respiratory depression [19,20].

The main objective of this study is to evaluate whether the use of two major opioids has an impact on improving pain and quality of life in cancer patients, taking into account the pharmacodynamics and pharmacokinetics of opioids, and the individual as a whole.

As a secondary objective, we intend to investigate the impact of this combination on the frequency and intensity of side effects associated with treatment, such as nausea, constipation and sedation, to determine whether the combination of opioids offers better tolerability to treatment and consequently better quality of life.

Methods

A bibliographic search was carried out in the databases PubMed/MEDLINE, Database of Abstracts of Reviews of Effects, The Cochrane Library, National Guideline Clearinghouse, National Health Service (NHS) Evidence and Index das Revistas Médicas Portuguesas.

The selection of articles and other related documents was made using equations with the following terms Medical Subject Headings (MeSH): “analgesics, opioid [pharmacological action]” and “cancer pain” and “quality of life”. In addition, the Summaries of Medicine Characteristics (SPC) of all opioids available in Portugal, through a search on the website of the National Authority for Medicines and Health Products (INFARMED), as well as the pharmacokinetic and pharmacodynamic characteristics of these medicines registered in DrugBank®, were also included.

Inclusion Criteria

Articles and other documents published between January 1, 2010 and June 1, 2023, in English, Portuguese and Spanish
Original articles, meta-analyses, systematic reviews and clinical guidelines, whose content corresponded to the research objectives.

Exclusion Criteria

Excluded non-systematized literature reviews and publications that did not address pharmacokinetic and pharmacodynamic characteristics of opioid medications or address the treatment of non-cancer pain
Articles and documents in languages other than Portuguese, English or Spanish.

Quality Assessment

To assess the quality and interest of the articles, the title and summary of the article were initially read, excluding those that were not related to the topic. Subsequently, the remaining articles were read in full, checking which ones met the established inclusion criteria and which ones contributed relevant information to carry out this review.

The search process began with a search in PubMed/MEDLINE, where specific criteria were applied, resulting in 342 articles related to the topic of interest. To refine the selection, aspects such as publication period, language and the journals involved were considered. After this initial filtering, the number of articles was reduced to 167, making the selection more manageable. From this list, new criteria were applied, including the exclusion of articles that addressed non-cancer pain, culminating in a final selection of 96 relevant articles. After a detailed analysis of the introduction and objectives of these articles, 13 remained for final review.

At the same time, an additional search was carried out in the NHS (UK National Health Service), which initially generated 37 results. However, further analysis revealed that only one article contained relevant information, but even this did not provide useful data for the study. Therefore, research in the context of the NHS did not make significant contributions to the objective of the investigation.

In the Cochrane Library database, the initial search resulted in 63 articles. Applying the cancer pain criterion, this number was reduced to 13, and, after reading the abstracts, none of the articles were considered useful.

Finally, the search in the National Guideline Clearinghouse (NGC) identified 54 articles, all focused on chronic pain, but outside the oncological context, therefore not presenting relevant contributions to the research objective.

The flowchart of the research method followed to select the articles chosen to be included in this study is represented in Figure 1.

Results

The simultaneous use of two major opioids is a practice that has become common. The rationale for combination therapy with major opioids is based on the assumption that it improves analgesia, limits the development of opioid tolerance, and decreases adverse effects [13]. The European Association for Palliative Care (EAPC) recommendations on opioids in cancer pain identified the practice of opioid combination therapy as an important area [13].

Even opioids considered highly selective for the μ-receptor bind to a large number of μ-opioid receptor subtypes (μ1, μ2) with the different opioids producing slightly distinct pharmacological responses based on the activation profiles of the μ-receptor subtypes [8]. Although each opioid receptor may mediate its effect independently, a growing body of evidence has accumulated for the existence of cellular or molecular interactions between types of opioid receptors [8,18,19,20].

Opioid μ receptor agonists have been used to form multitargeted ligands, which improve the therapeutic index of the analgesic relative to potent μ receptor monovalent agents. Receptor subtypes are likely receptor dimers capable of altering receptor signaling and trafficking relative to monomers. Different opioids produce distinct effects through unique conformational changes of the opioid receptor, differences in interactions with G proteins, receptor phosphorylation, and β-arrestin activity [23]. As a consequence, allosteric modulation, ligand signaling bias, and μ-opioid receptor subtypes or dimers may contribute to providing a rational basis for combining opioids in an attempt to improve clinical response [18,19].

Morphine, compared to other opioids, has a high activity-to-endocytosis ratio, which may prolong signaling with prolonged exposure. Coadministration with other opioids (such as Fentanyl) can increase the internalization of the µ receptor and potentiate the analgesic effect of morphine. However, the combination of certain opioids does not always result in synergy, and the effects vary depending on the characteristics of the medications involved [19,24].

Combining opioids may result in analgesic synergy, allowing the use of lower doses of each drug to achieve effective pain control, which may reduce the incidence of adverse effects such as constipation and nausea [25,26].

Combination Between Oxycodone and Morphine

The combination of oxycodone with morphine is based on the premise that oxycodone acts on κ receptors, promoting the upregulation of µ receptor expression, synergistically increasing the clinical efficacy of the opioid, since analgesia will occur through the activation of κ and µ [27].

In a clinical study, rescue morphine consumption was significantly reduced (38%) in patients receiving a combination of morphine and oxycodone compared to those receiving morphine alone. The synergistic effect between the two was evident during the first week of oxycodone treatment. The authors concluded that the combination of morphine and oxycodone may be a useful alternative to morphine alone, with a better analgesic profile and fewer central nervous system side effects (nausea, vomiting, and sedation). Furthermore, the combination of the two improved pain relief without causing significant adverse effects such as respiratory depression [28].

A double-blind clinical trial evaluated the efficacy and safety of morphine and oxycodone in 22 cancer patients suffering from moderate to severe pain. Patients received monotherapy with controlled-release (CR) formulations of morphine or oxycodone along with immediate-release rescue morphine. After four weeks, the average daily consumption of morphine was 60 to 90 mg, while that of oxycodone varied between 20 and 60 mg. Pain relief was comparable between the two groups, but the dose of morphine used as rescue was 38% higher in the group that received morphine alone. The expected benefits of the morphine/oxycodone combination versus monotherapy include a reduced incidence of moderate to severe adverse effects, especially nausea, vomiting, and central nervous system side effects [29].

One study demonstrated that the severity of nausea and vomiting, however, was less with the morphine/oxycodone combination, and the incidence of oxygen desaturation was greater in patients receiving morphine alone. Furthermore, combination therapy demonstrated better tolerability, with patients experiencing fewer side effects compared to those receiving morphine alone. These findings suggest that the combination of morphine and oxycodone may improve pain control outcomes by maximizing analgesic efficacy and minimizing the risk of adverse effects, making it a potentially superior approach to monotherapy in treating cancer pain [30], especially when associated with reductions in healthcare costs related to adverse effects [31].

Combination of Spinal Morphine and Systemic Buprenorphine

The combination of spinal morphine and systemic buprenorphine may have clinical value as these opioids interact at different levels due to their distinct receptor activities. The antagonistic effects of buprenorphine have been observed only at high doses exceeding therapeutic ranges. When administered together, spinal morphine and systemic buprenorphine produce a greater analgesic effect than expected based on individual dose-response curves [19]. The hypothesis is that buprenorphine, by blocking κ receptors, facilitates the action of morphine on µ receptors [27]. Recent study suggests that buprenorphine may limit hyperalgesia by inhibiting descending facilitation mediated by dynorphin expression in the spinal cord [19].

Combination of Transdermal Fentanyl and Oral Morphine

Conversion from 300 µg/h transdermal Fentanyl to 150 µg/h, along with 360 mg oral morphine, resulted in not only adequate pain relief but also the elimination of neuroexcitatory adverse effects. These findings suggest that the combined approach can optimize the treatment of cancer pain, providing an improvement in patients' quality of life. Appropriate choice of dosages and careful monitoring are essential to maximize the benefits of this therapeutic combination [19].

In a prospective, randomized clinical study, two different treatment methods were compared, considering two major opioids (transdermal fentanyl and oral oxycodone) in 32 patients with moderate cancer pain. Patients who received the combination of transdermal Fentanyl and oral Oxycodone had significantly less sedation [32].

In a prospective, randomized clinical study, but not double-blind, phase II study aimed to test two different treatment methods: opioid rotation and combination of two main opioids. It is concluded that both opioid rotation and combination strategies appear to provide significant pain relief and patient satisfaction. The combination of transdermal fentanyl and oral oxycodone was well tolerated by cancer patients. It is possible that the synergistic analgesic effect results from the simultaneous activation of µ and κ opioid receptors. The incidence of adverse events was similar; however, more patients experienced constipation with the opioid combination (42%) than with rotation (17%; p = 0.05), two different treatment methods were compared, considering two major opioids (transdermal fentanyl and oral oxycodone) in 32 patients with moderate cancer pain. Patients who received the combination of transdermal Fentanyl and oral Oxycodone had significantly less sedation [20].

Another study of cancer patients evaluated various doses of oral morphine in patients who were receiving increasing doses of transdermal fentanyl or methadone for pain control. The addition of oral morphine to patients receiving fentanyl or methadone significantly decreased pain intensity (P < 0.05) without any increase in opioid-related adverse effects. In the fentanyl with morphine group, pain intensity decreased significantly (P < 0.05) from baseline to week 5. When added to fentanyl, the daily dose of morphine required for significant pain improvement decreased over the 5 weeks, but this was not observed when morphine was added to methadone [33].

A multicenter, randomized, phase IV study evaluated the efficacy and tolerability of the combination of transdermal fentanyl with oral oxycodone in patients with cancer pain. After one week of treatment, both groups showed a significant improvement in pain scores, with 62% of patients in the combination group reporting relief, compared to 42% in the opioid rotation group, although this difference was not statistically significant. The synergistic interaction between fentanyl, which binds to the µ receptor, and oxycodone, a possible Ƙ receptor agonist, may explain the observed analgesic effect. Highlighting the importance of individualizing opioid therapy, taking into account both efficacy in pain relief and tolerance to adverse effects, this study suggests that both opioid rotation and combination therapy are valid strategies that should be discussed with patients [34].

Discussion and Conclusions

Opioids are essential in the treatment of moderate to severe pain in cancer patients [16,29]. The response to these medications is influenced by several factors, resulting in significant both intraindividual and interindividual variability [19].

It is essential that, for its use, the characteristics of each opioid must be taken into account (pharmacokinetics, pharmacodynamics, toxicity, drug interactions) and know that these will have to be combined according to the patient's characteristics (age, sex, genetics, tumor primary and metastases, comorbidities, simultaneous treatments, organ function, types of pain, psychological structure, allergies, among others) [9,14,15].

In clinical practice, the main goal is to globally reduce pain with minimal side effects. However, dynamic aspects over time, such as dose adjustments, substitution with other opioids, and addition of synergistic analgesics, are equally crucial to ensure adequate and personalized efficacy and safety [16,17,29,31].

The combination of opioids is based on the premise that different opioids act through different mechanisms, which can result in a reduction in adverse effects associated with the dose [18]. The combined use of two major opioids may lead to smaller increases in the equivalent dose of the second opioid, with improvements in analgesia and reductions in adverse effects such as nausea, vomiting, and constipation [19,20,28,32,33].

It is crucial to pay attention to accurate dose titration of each opioid rather than relying solely on crude conversions of equianalgesic doses [13].

Opioid therapy must be individualized so that each dose provides a balance between effective pain control and acceptable adverse effects. To achieve this goal, both opioid rotation and combination therapy can be tried for all patients as they appear to provide significant pain relief and patient satisfaction [32]. Potential benefits and risks should be discussed with patients [31].

The combination of transdermal fentanyl with other opioids can be considered a viable option for cancer pain (level of evidence 2), providing effective pain control and the disappearance of neuroexcitatory adverse effects [19,20].

Combining buprenorphine with another opioid has also been shown to have clinical value (level of evidence 2) because these opioids can interact at different levels due to their differences in receptor activity. Its concomitant administration produces a greater antinociceptive effect than could have been predicted from individual dose-response curves. κ receptor blockade by systemic buprenorphine has been shown to play a role in providing superadditive analgesia with spinal morphine [19].

Oxycodone combined with rescue morphine resulted in significant reductions in the incidence of nausea and vomiting. These results suggest a synergistic effect when the combination of morphine and oxycodone was used [24,27]. Furthermore, combination therapy demonstrated better tolerability, with patients experiencing fewer side effects compared to those receiving morphine alone. These findings suggest that the combination of morphine and oxycodone can improve pain control outcomes, maximizing analgesic efficacy and minimizing the risk of adverse effects, making it a potentially superior approach to monotherapy in the treatment of cancer pain (level of evidence 3) [31,32].

However, the impacts on quality of life, although promising, require further investigation, given that current evidence is still insufficient to recommend a standard combination of opioids in clinical practice.

Although there is controversy regarding the effectiveness of opioid combination therapy in controlling cancer pain, and with weak recommendation (based only on levels of evidence 2 and 3), patient monitoring for pain control and quality of life Continuous reassessment are the keys to providing adequate pain relief, mitigating adverse effects, and increasing patients' quality of life.

Limitations and Future Perspectives

The studies consulted on the combination of opioids have small samples, low methodological consistency and short follow-ups, presenting limited levels of evidence (2 or 3).

There are challenges in titrating and rotating opioids that are difficult to control, given that there is no determination of the exact dose titration of each opioid, as different opioids have different potency in different patients and equianalgesic conversion does not always result in linear benefits.

The lack of personalized treatment strategies for patients with cancer pain continues to be a challenge that limits the effectiveness of opioid use. The variability in response to treatment points to the urgent need for more individualized approaches to optimize pain relief and minimize adverse effects. In the future, precision medicine emerges as the most promising strategy, with the potential to integrate advances in pharmacogenomics, to precisely adjust therapies, according to the genetic profile of each patient, thus improving the management of cancer pain.

The search for new opioids with reduced adverse effects, especially with regard to opioid-induced ventilatory deficit and addiction potential, has advanced steadily over the past decade, after a pause at the end of the 20th century. This progress is the result of a deeper understanding of the molecular pharmacology of these medicines, driven by the genomic revolution.

The future should bring more atypical opioids, with a more detailed study of biased agonism as we deepen our understanding of intracellular events. The development of sophisticated medicines and new heterodimers is also expected, as well as further exploration of opioimmunopharmacology to better understand the actions of opioids.

Innovations in opioid formulation are underway with the goal of reducing side effects and improving efficacy. New delivery systems, such as extended-release matrix tablets, which use various polymers to modulate drug release, are in line with innovations aimed at optimizing opioid formulations and promoting more effective pain management. These promising alternatives aim to improve pain control and minimize the need for high doses.

Additionally, patches and controlled-release methods have the potential to reduce side effects and improve efficacy, allowing for more efficient pain control at lower doses.

Another good chance for the future will be the digital analgesic, controlled by a second generation Artificial Intelligence (AI) system, optimizing the dosage of opioids instantly, reducing side effects and increasing effectiveness.

Funding

This research was supported by National Funds through FCT—Fundação para a Ciência e Tecnologia, I.P., within CINTESIS, R&D Unit (reference UIDB/4255/2020) and within the scope of the project RISE, Associated Laboratory (reference LA/P/0053/2020). The Centre for Innovative Biomedicine and Biotechnology (CIBB) and the Institute for Clinical and Biomedical Research (iCBR) are supported by the Foundation for Science and Technology (FCT), Portugal, through the Strategic Projects UIDB/04539/2020 (10.54499/UIDB/04539/2020) and UIDP/04539/2020 (10.54499/UIDP/04539/2020) and Associated Laboratory funding LA/P/0058/2020 (10.54499/LA/P/0058/2020). The present work was supported by ACIMAGO (Project 03/21).

Institutional Review Board Statement

The study was conducted in accordance with the Declaration of Helsinki, and approved by the Ethics Committees of the Faculty of Medicine of the University of Coimbra.

Informed Consent Statement

Informed consent was obtained from all subjects involved in the study or their legal representatives.

Data Availability Statement

The data presented in this study are available on request from the corresponding author.

Conflicts of Interest

The authors declare no conflict of interest.

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Figure 1. Process followed in bibliographic research. The bibliographic search was carried out in the PUB MED/MEDLINE, Cochrane Library NHS and NGC databases.

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